Few studies have assessed the actual costs associated with failure of initial empiric antibiotic therapy administered to patients with community-acquired intra-abdominal infections. The goals of this study were (i) to determine the frequency of unsuccessful initial empiric therapy in a real-world setting and (ii) to determine the associated impact on medical costs. Thus, a retrospective chart review was performed at four acute-care university hospitals in France. A total of 292 patients hospitalized for community-acquired intra-abdominal infection were included. The mean age of the cohort was 51 years, and 42% of the patients were female. The most commonly administered empiric regimens were intravenous amoxicillin/clavulanate alone (69 patients) or in combination with other antibiotics ( n=87) and piperacillin/tazobactam alone ( n=24) or in combination ( n=48). Other regimens included broad-spectrum penicillin, cephalosporins, and fluoroquinolones administered alone or in combination ( n=64). Empiric therapy was successful in 189 (65%) patients and unsuccessful in 103 (35%). Among the 292 patients with community-acquired infection, 15 died of the infection, 8 required reoperation and 80 required second-line antibiotic therapy. Patients with unsuccessful initial empiric therapy had significantly more parenteral antibiotic days (10.3 vs. 7.6 days) and a longer length of stay (16.2 vs. 12.8 days) compared to those with successful initial empiric therapy. A better selection of initial empiric antibiotic therapy may significantly influence the medical costs associated with patients who are hospitalized with community-acquired intra-abdominal infections.