Inclusion Criteria

• Must have cellulitis as defined here:

  1. Definition A (preferred definition):

     Recent onset of soft tissue erythema, considered by the treating clinician to be bacterial in origin, and associated with signs of infection that include at least two of the following: pain, swelling, warmth, fever, lymphangitis, induration, or ulceration.

  2. Definition B (ONLY for darkly-pigmented subjects who cannot use Definition A):

     Recent onset of soft tissue color change, pain, or swelling, considered by the treating clinician to be bacterial in origin, and at least one of the following: warmth, fever, induration, or ulceration

• Clinical (non-research) attending physician agrees with treatment with cephalexin until 3 days after all symptoms gone, using our weight-based dosing
• Responsible clinical attending physician comfortable with adding trimethoprim-sulfamethoxazole vs. placebo to the above
• Subject understands the study and signs written informed consent.
• Subject agrees to drink at least 1 liter of fluid per day.
• Subject will commit to all follow-up appointments

Exclusion Criteria:

• Age < 12 months or weight <15 kg
• Current skin infection has already been treated
• Allergy to sulfa drugs
• History of severe allergic reaction to penicillin (defined as anaphylactoid reaction, angioedema, bronchospasm)
• Current use of any antibiotic (other than topicals)
• Diabetes mellitus
• Cellulitis complicated by underlying peripheral vascular disease
• Renal insufficiency, defined as patient report, clinical suspicion, or creatinine>1.3 or EGFR<60 on the last-available set of chemistry results in our computer system
• Hospital admission required
• Presence of > 1 cc of purulent discharge at any time
• Cellulitis involving an indwelling vascular, enteric, or urinary catheter
• Immunocompromise of any etiology
• Pregnancy
• Breast feeding
• Facial cellulitis (infection is above the clavicles)
• Cellulitis associated with marine or freshwater injury, or animal or human bite. (Insect bites not excluded.)
• History of glucose-6-phosphate dehydrogenase deficiency
• Taking coumadin (warfarin), methotrexate, cisapride, phenytoin (dilantin), digoxin, or dofetilide
• Known megaloblastic anemia due to folate deficiency.