To assess the need for antibiotics in low-risk human bite wounds, a prospective, double-blind, placebo-controlled study involving 127 patients presenting with low-risk human bite wounds over 2 years to a 40,000 visit per year major academic ED was performed. Low-risk bites penetrated only the epidermis and did not involve hands, feet, skin, overlying joints, or cartilaginous structures. Exclusion criteria included age less than 18 years, puncture wounds, immunocompromise, allergy to penicillin or related compound, or bites greater than 24 hours old. Patients were randomly assigned to receive either a cephalexin/penicillin combination or placebo. One hundred twenty-five patients completed the study. Infection developed in 1 of 62 patients receiving placebo (1.6%, 95% confidence interval CI, 0-7.3%). Infection developed in 0 of 63 patients receiving the cephalexin/penicillin combination (0%, 95% CI, 0-4.6%). Antibiotic treatment of some low-risk human bite wound could be unnecessary. Infection rates appear similar in low-risk human bite wounds whether treated with antibiotics or placebo.