Diabetic patients with foot infections were prospectively evaluated over a two-year period. Cultures from reliable specimens avoiding contamination with foot ulcers were obtained in 54 infectious episodes. Staphylococcus species, Enterococcus species, Corynebacterium species, and various species of Enterobacteriaceae were commonly isolated. Common anaerobic isolates included Peptostreptococcus magnus, Peptostreptococcus prevotii, and Bacteroides species. Results of cultures from 94 unreliable specimens were similar. Results of reliable and unreliable specimens obtained simultaneously in 26 patients agreed in seven (27%), but antibiotics selected for organisms isolated from unreliable specimens would have adequately covered pathogens found in the reliable culture in 24 (93%). Diabetic foot infections usually involve mixed bacterial flora, including aerobic, facultatively anaerobic, and anaerobic microorganisms. Specimens should be obtained from infected tissue that does not communicate directly with the foot ulcer if possible. If such specimens are not available, cultures of purulent exudate within the foot ulcer or soft-tissue sinuses may provide useful information on which to base decisions about antibiotic therapy. Broad-spectrum beta-lactam antibiotics or a combination of antibiotics active against facultatively anaerobic cocci and bacilli as well as anaerobes provide the best empirical antimicrobial coverage in these patients.