Inclusion Criteria:

1. Males or females with a suspected or histologically confirmed* index oral premalignant lesion (excluding carcinoma in situ), 12mm or greater in size that has not been biopsied in the past 6 weeks. Each index lesion must be either a dysplastic measurable leukoplakia or erythroplakia in the oral cavity or accessible oropharynx, or hyperplastic leukoplakia of high-risk sites, lateral and ventral tongue and floor of mouth.
2. (Continued) * Patients will be registered using a two-stage registration process. The first stage of registration will be completed on the day of informed consent. The second stage of registration will be completed once the biopsy has been histologically confirmed to contain dysplasia.
3. The subject is >/= 18 years of age. Because no dosing or adverse event data are currently available on the use of rosiglitazone in participants <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
4. The subject's life expectancy is > 12 weeks and Karnofsky performance score is 70-100%.
5. The subject meets the following laboratory eligibility criteria during a time not to exceed 4 weeks prior to going on study: Hemoglobin and hematocrit levels above the lower limit of normal. White blood cells >/= 3,000/mL, Platelets >/= 125,000/mL, Total bilirubin </= 1.5 times Upper Limit of Normal (ULN), aspartate aminotransferase (AST or SGOT)/alanine aminotransferase (ALT or SGPT) </= 1.5 times ULN, blood urea nitrogen (BUN) and serum creatinine </= 1.5 times ULN, Lactic acid dehydrogenase (LDH) </= 1.5 times ULN
6. If the subject is female and of childbearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile), she: - has been using adequate contraception (abstinence, IUD, birth control pills, or spermicidal gel with diaphragm or condom) since her last menses and will use adequate contraception during the study, AND - is not lactating, AND - has a documented negative serum pregnancy test within 14 days prior to randomization.
7. The subject has discontinued any other oral cancer chemopreventive therapy at least 12 weeks prior to the Baseline visit and all toxicities have been fully resolved. Daily aspirin is permitted.
8. The subject is willing and able to fully participate for the duration of the study.
9. If applicable, the subject has been counseled on smoking cessation
10. The effects of Avandia on the developing human fetus at the recommended therapeutic dose are unknown. For this reason,& because Avandia has been associated with fetal death & growth retardation in rats & rabbits & placental pathology in rats, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry & for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately & will be removed from the trial.
11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. The subject has active cancer or carcinoma in situ of the head and neck
2. The subject has a contraindication to biopsy
3. The subject is of New York Heart Association (NYHA) Class I to IV heart failure, as well as, any patients with known heart failure.
4. The subject has a history of myocardial infarction, angina, or coronary artery disease within the past 6 months, or active cardiac disease.
5. The subject exhibits clinical evidence of active liver disease, history of chronic liver disease or edema.
6. The subject is a diabetic not on treatment or hyperglycemic (has a random blood glucose level >200 mg/dl). The subject currently receives insulin, sulfonylurea or metformin (doses of rosiglitazone greater than 4 mg daily in combination with these therapies are not currently indicated. Because this protocol uses the maximum recommended dose of 8 mg daily, subjects on insulin, sulfonylurea or metformin will be ineligible for participation in this trial). The subject is currently receiving thiazolidinediones.
7. The subject is currently receiving medical therapy for dysregulated blood sugar.
8. The subject has experienced jaundice with Rezulin® (troglitazone)
9. The subject has known hypersensitivity to Rosiglitazone, Avandia, or any of its components
10. The subject has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC)
11. The subject has a history of invasive cancer within the past 18 months (excluding non-invasive bladder cancer, non-melanoma skin cancer and in situ cervical cancer). Subjects (excluding those with a history of colorectal cancer, Familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)) who received curative treatment and have shown no evidence of recurrence for 18 months will be eligible.
12. The subject has had chemotherapy, immunotherapy, hormonal therapy (other than hormone replacement therapy for menopause), or radiation therapy within 18 months of the Baseline visit.
13. The subject will need concurrent chemotherapy, radiotherapy, hormonal (other than HRT for menopause), or immunotherapy during the time of study.
14. The subject has received any investigational medication within 30 days of the Baseline visit or is scheduled to receive an investigational drug during the course of the study.
15. The subject participated in the study previously and was withdrawn.
16. The subject is pregnant or nursing
17. Subjects who have had the study drug prior to this study
18. The subject has uncontrolled intercurrent illness including: ongoing or active infection, HIV, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements