In this prospective, randomized, open-label clinical trial, we compared the efficacy and safety of two antibiotic regimens for severe diabetic foot infections (DFI). Sixty-two in-patients with DFI received either piperacillin/tazobactam (Pip-Tazo, n = 30) (4.5 g intravenously every 8h) or imipenem/cilastatin (IMP, n = 32) (0.5 g intravenously every 6h). The mean duration of treatment was 21 days for Pip-Tazo and 24 days for IMP. Twenty-two (73.3%) patients in the Pip-Tazo group and 26 (81.2%) patients in the IMP group had DFI associated with osteomyelitis. Successful clinical response was seen in 14 (46.7%) patients in the Pip-Tazo group and in nine (28.1%) patients in the IMP group [relative risk (RR) 1.6 (95% CI 0.84-3.25), p 0.130]. Two patients in the IMP group and none in the PIP-Tazo group relapsed [RR 2 (0.94-4.24), p 0.058]. Eighty-nine microorganisms were isolated: 38 (43%) Gram-positive and 51(57%) Gram-negative. Among patients with positive culture, 47 (96%) had complete and two (4%) had partial microbiological response. Microbiological response rates were similar in both groups (p 1.000). Amputation was performed in 18 (60%) and 22 (69%) patients in the Pip-Tazo and IMP groups (p 0.739) respectively. Side effects were more common in the Pip-Tazo group (30% vs. 9.4%), but they were generally mild and reversible. In conclusion, although the sample size was small and the results did not reach statistical significance, Pip-Tazo produced a better clinical response rate than IMP in the treatment of severe DFI. There was no significant difference between the treatment groups with respect to microbiological response, relapse and amputation rates.