Perfusion of the peritoneal cavity with chemotherapy agents under hyperthermic conditions has been utilized by several investigators in the treatment of intra-abdominal malignancies. Based on the concept that hyperthermia may potentiate the cytotoxic effects of chemotherapeutic agents, we embarked on a clinical trial of two-stage peritoneal chemotherapy for patients with primary peritoneal mesothelioma, a neoplasm unresponsive to traditional systemic chemotherapeutic regimens. In stage I, patients underwent surgical debulking of gross disease and placement of an intraperitoneal infusion catheter, through which intraperitoneal chemotherapy was administered for four months. Stage II consisted of debulking of residual tumor, placement of two transabdominal perfusion cannulae and administration of high-dose intraperitoneal chemotherapy at 40 degrees C using a simple, disposable perfusion circuit. Flow rates were maintained at 1 l/min, and inflow and outflow temperatures maintained at 42 and 40 degrees C, respectively. To date, three patients have undergone both phases of the protocol, with no perioperative complications related to either hyperthermia or end-organ toxicity. One patient died of progressive disease after three months, and two patients are alive and well. One patient developed a small bowel anastomotic leak three weeks after operation. In summary, intraoperative hyperthermic peritoneal chemotherapy may play a role in novel approaches to the treatment of peritoneal malignancies previously unresponsive to traditional chemotherapeutic regimens.