BACKGROUND Systemic inflammatory response syndrome (SIRS) is characterized by systemic inflammation and tissue injury. Secondary sepsis is a common critical illness associated with poor clinical outcome. The aim of this study was to investigate the risk of SIRS-positive and SIRS-negative sepsis following gastrointestinal (GI) perforation. MATERIAL AND METHODS A retrospective study included 51 patients with GI perforation who had clinical evidence of sepsis, with or without SIRS. Clinical outcome was assessed at day 30 using the Glasgow Outcome Scale (GOS) (score, 1-5) and the sequential organ failure assessment (SOFA) (score, 1-6) to determine organ function. RESULTS Fifty-one patients were included in the study (median age, 74 years; 37 male patients); 20 patients (39.2%) developed secondary sepsis; 16 patients (80%) had SIRS-negative sepsis; four patients had SIRS-positive sepsis. An increased SOFA score was a significant independent predictor of GI perforation with sepsis (5.4±3.1 vs. 1.5±2.8) (P<0.0001). Patients with GI perforation with SIRS-negative sepsis had a significantly less favorable outcome (5/16 vs. 2/35) (P=0.03). The risk of SIRS-negative sepsis following GI perforation was 39.2%, and the risk of mortality for SIRS-negative sepsis was 31.3%. In the Cox regression analysis, septic shock and septic encephalopathy were associated with a worse clinical outcome. CONCLUSIONS The findings of this study support the recognition of SIRS-negative sepsis following GI perforation as an important condition to recognize clinically, given its association with increased patient morbidity and mortality.