<p><b>OBJECTIVE</b>To explore the distribution and antibiotic resistance of pathogens in lesions of diabetic foot osteomyelitis (DFO) and analyze the risk factors causing osteomyelitis.</p><p><b>METHODS</b>A total of 372 patients with diabetic foot infections hospitalized between January 2011 and December 2014, including 203 with osteomyelitis (OM group) and 169 without osteomyelitis (non-OM group), were examined for the distribution and antibiotic resistance profile of the pathogens in the wounds. Logistic regression analysis was used to analyze the risk factors causing osteomyelitis.</p><p><b>RESULTS</b>Gram-negative bacteria were the predominant pathogens (53.7%) in the infected wounds in OM group, whereas Gram-positive bacteria were the most frequently found (56.7%) in non-OM group (P=0.001). Among the Gram-positive bacteria, Staphylococcus was the dominating flora (35.1%). The resistance rate to oxacillin and cefoxitin of the isolated bacteria in OM group (64.9% and 68.5%, respectively) was significantly higher than that in non-OM group (29.2% and 32.6%, respectively; P<0.05). Among the gram-negative bacteria, Enterobacteriaceae was the dominating flora (62.4%), with a higher resistance rate to Cefepime and Aztreonam in OM group (30.1% and 38.6%, respectively) than in non-OM group (15.1% and 22.2%, respectively; P<0.05). Logistic regression analysis indicated that the infection by multi-drug resistant bacteria and an wounds area >4 cm(2) were the risk factors for osteomyelitis in patients with diabetic foot infections (P<0.05).</p><p><b>CONCLUSION</b>In addition to an empirical anti-infection therapy, clinicians should choose specific antibiotics against Gram-negative bacteria according to the microbial spectrum and antibiotic resistance of pathogens in patients with DFO; patients with diabetic foot infections by multi-drug resistant bacteria and those with a wound area exceeding 4 cm(2) are exposed to an increased risk of osteomyelitis.</p>