The use of prophylactic low-dose penicillin acutely burned, hospitalized patients remains controversial. Fifty-one adult patients with burns of 1% to 91% total body surface area were prospectively studied to determine the efficacy of prophylactic penicillin in the prevention of wound cellulitis and burn wound sepsis, and to examine the influence of prophylactic penicillin on the emergence of antibiotic resistant microorganisms. In 25 patients given a 5-day course of penicillin prophylactically, 11 developed cellulitis and two had burn wound sepsis. A similar group of patients given placebo developed seven cases of cellulitis and three cases of burn wound sepsis (p = 0.340). No patient in either group developed gentamicin-resistant Gram-negative organisms, although the gastrointestinal tracts of two patients in the penicillin group showed new colonization by yeast. We conclude that the routine administration of prophylactic penicillin neither protects against cellulitis and burn wound sepsis, nor promotes selection of antibiotic-resistant bacteria in hospitalized patients with acute thermal injury.