OBJECTIVES: Diabetic foot infections (DFI) account for more hospital days than any diabetes-related diagnosis. Many patients with DFI are Medicare-eligible, and hospitals are motivated to decrease costs without altering patient outcomes. A large, multicenter, randomized, double-blind trial (SIDESTEP) comparing ertapenem (1 g QD) and piperacillin/tazobactam (3.375 g QID) found equivalent efficacy in the treatment of DFI. METHODS: Individuals enrolled in SIDESTEP, treated entirely as inpatients, and clinically evaluable at final assessment (10 days after completing antibiotic therapy; n = 99) were included. Cost per dose was calculated from a) average actual hospital acquisition price/dose (IMS Health, National Sales Perspectives) for 2005 in U.S. dollars for ertapenem ($40.52) or piperacillin/tazobactam ($13.58); b) average U.S. wage and benefits for labor, based a review of 10 time-and-motion studies of intravenous antibiotic drug preparation and administration ($3.03); and c) consumable supplies, using a 40% discount off manufacturer list price in the 2005 Redbook ($2.52). For each patient, actual doses (either ertapenem or piperacillin/tazobactam) was multiplied by total cost per dose (ertapenem = $45.23; piperacillin/tazobactam = $19.13). RESULTS: No differences with respect to demographics, mean length of treatment or wound severity were noted (intravenous therapy days: ertapenem = 6.6; piperacillin/tazobactam = 6.4); (wound severity: ertapenem = 29%; piperacillin/tazobactam = 26% severe). Differences were significant with respect to mean doses of active drug (ertapenem = 7.6; piperacillin/tazobactam = 25.7; p <0.0001) and costs (ertapenem = $352.11; piperacillin/tazobactam = $491.20; p = 0.018). The $139.10 difference between groups accounts for approximately 3% of total hospital DRG reimbursements for Medicare patients. CONCLUSIONS: Once-daily dosing of ertapenem offers the advantage of less cost to hospitals, compared to QID dosing for piperacillin/tazobactam, without compromising efficacy or safety.