Persistent or recurrent peritoneal carcinomatosis (PC) documented at second-look surgery has proved relatively refractory to second-line therapy. The majority of these tumors do not respond to cisplatin based chemotherapy. Because of the relatively high response rate we observed with systemically administered mitomycin C plus 5-fluorouracil, we initiated a trial of intraperitoneal (IP) mitomycin C (10 mg/m2 in 2 L dialysate fluid every 4 weeks) in 14 patients with refractory PC secondary to gynecologic malignancies. All but one patient had PC secondary to ovarian cancer documented at second-look cytoreductive surgery following intense cisplatin based drug therapy. One patient had endometrial cancer and had been treated previously with radiation. In all, 49 courses of intraperitoneal mitomycin C were administered to 14 patients. Systemic toxicity was minimal, except for mild thrombocytopenia that occurred in four patients. However, abdominal pain due to chemical peritonitis was cumulative and dose limiting after three to five courses of therapy. Of the seven patients with measurable disease (positive serum CA-125 or intraperitoneal cytology), six had normalization of at least one of these two parameters. Eight of the 14 patients remain alive without clinical evidence of disease with a median follow-up duration of 10 months. We conclude that IP mitomycin C is a well-tolerated and potentially effective treatment modality in patients with limited PC following second-look surgical debulking for gynecologic malignancy.