© Mary Ann Liebert, Inc. 2014. Background: In patients with intra-abdominal infection, inappropriate initial empiric antibiotic therapy is associated with greater morbidity. We evaluated the impact of adequate empiric antibiotic treatment together with control of the infection focus on the morbidity and mortality rates of patients with secondary peritonitis. Methods: This was a prospective, observational study with the participation of 24 Spanish hospitals and 362 patients with secondary peritonitis (262 community-acquired, 100 post-operative). Therapeutic failure (infectious complications or death) was classified into four categories according to whether empiric antibiotic treatment was appropriate and the infection focus was controlled. Results: The rates of therapeutic failure, re-operation, and mortality were 48%, 13%, and 8%, respectively. Empiric antibiotic treatment was inappropriate in 39% of cases, which was associated with a higher rate of surgical site infection (53% vs. 40%; p=0.031) and death (12% vs. 5%; p=0.021) than was observed in patients receiving appropriate initial empiric therapy. Eight percent of patients in whom control of the infection focus was not obtained suffered from more infectious complications (76% vs. 52%; p=0.01) and surgical site infections (69% vs. 44%; p=0.01); and in this group, both therapeutic failure and mortality rates were similar, independent of whether the empiric antibiotic therapy was appropriate. Conclusion: Inappropriate initial empiric antibiotic therapy was associated with higher rates of therapeutic failure, surgical site infection, re-operation, and death. Classification of therapeutic failure into four categories according to the appropriateness of empiric antibiotic therapy and the success of infection control provided excellent discrimination of morbidity and death.