Background A recent prospective, multicenter, randomized controlled trial found that 4 days of antibiotics after source control of complicated intra-abdominal infections resulted in similar outcomes when compared with longer duration. We hypothesized that the subset of patients presenting with sepsis have similar outcomes when treated with the shorter course of antibiotics. Study Design Patients from the STOP-IT (Study to Optimize Peritoneal Infection Therapy) trial database meeting criteria for sepsis (ie, temperature <36°C or >38°C and a WBC count <4000 cells/mm3 or >12,000 cells/mm3) were analyzed. Patients had been randomized to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 calendar days of therapy (n = 45), or to receive a fixed short-course of antibiotics for 4 ± 1 calendar days (n = 67). Outcomes included incidence of and time to surgical site infection, recurrent intra-abdominal infection, Clostridium difficile infection, and extra-abdominal infections, as well as hospital days and mortality. Results One hundred and twelve of the 588 patients in the STOP-IT database met criteria for sepsis and were adherent to the protocol. With regard to short- vs long-course therapy, surgical site infection (11.9% vs 8.9%; p = 0.759), recurrent intra-abdominal infection (11.9% vs 13.3%; p = 1.00), extra-abdominal infection (11.9% vs 8.9%; p = 0.759), hospital days (7.4 ± 5.5 days vs 9.0 ± 7.5 days; p = 0.188), days to recurrent intra-abdominal infection (12.5 ± 6.6 days vs 18.0 ± 8.1 days; p = 0.185), days to extra-abdominal infection (12.6 ± 5.8 days vs 17.3 ± 3.9 days; p = 0.194), and mortality (1.5% vs 0%; p = 1.00) were similar. There were no cases of C difficile infection. Days to surgical site infection (6.9 ± 3.5 days vs 21.3 ± 6.1 days; p < 0.001) were fewer in the 4-day therapy group. Conclusions There was no difference in outcomes between short and long-course antimicrobial therapy in patients with complicated intra-abdominal infection presenting with sepsis. Our findings suggest that the presence of systemic illness does not mandate a longer antimicrobial course if source control of complicated intra-abdominal infection is obtained.