No standard effective treatment exists for peritoneal carcinomatosis of gastrointestinal origin. The pharmacokinetic advantage of intraperitoneal chemotherapy and the synergy of heat and certain anticancer agents have prompted researchers to investigate intraperitoneal hyperthermic chemotherapy in treating disseminated peritoneal cancers. We have conducted a large Phase II trial to determine the safety and efficacy of aggressive cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC) in treating peritoneal carcinomatosis of gastrointestinal origin. Patients with disseminated peritoneal carcinomatosis of gastrointestinal origin with or without malignant ascites were eligible. After aggressive surgical debulking, patients were administered a 2-hour heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. The major response variable monitored was overall survival. Patients were assessed for toxicity after IPHC administration using the National Cancer Institute Common Toxicity Criteria. Eighty-four patients with peritoneal carcinomatosis of gastrointestinal origin were evaluated for survival and toxicity (colon, n = 38; appendix, n = 22; stomach, n = 19; other gastrointestinal, n = 5). Thirty-nine (46%) patients had malignant ascites at the time of therapy. The operative mortality (30-day) was 6 per cent. Hematologic toxicity was the most common toxicity but was of mild to moderate severity (7 and 4% of patients had grade 3/4 white blood cell or platelet toxicity, respectively). The overall median survival was 14.3 months. The median survival of patients with peritoneal carcinomatosis of appendiceal, colorectal, and gastric origins were 31.1+, 14.6, and 10.1 months, respectively. Significant differences in median survival were seen in patients without and with malignant ascites (27.7 vs 7.6 months; P = 0.0004) and R0/R1 (complete gross tumor resection) versus R2 (gross residual tumor) surgical resection status (28.5+ vs 10.8 months, P = 0.0002). These data suggest that aggressive cytoreductive surgery with IPHC using mitomycin C is safe and effective in treating peritoneal carcinomatosis of gastrointestinal origin. Additional studies and broader applications of this treatment are encouraged.