Cisplatin (C) or carboplatin (CBP) plus cyclophosphamide (CTX) was until recently considered standard chemotherapy for advanced ovarian cancer (OC). Attempts to maximize platinum and its analog activity against OC include its administration directly into the peritoneal cavity. In the past we have shown that intraperitoneal (IP) CBP administration is a safe and effective treatment for OC [Polyzos et al: Proc Am Assoc Cancer Res 1990;31: 1120]. In the present study we aimed to compare the effectiveness and toxicity of CBP administration either intravenously (IV) or IP plus CTX IV. Since 1990, 90 evaluable patients with stage III OC were prospectively randomized to receive CBP 350 mg/m2 IV or IP plus CTX 600 mg/m2 IV (in both groups) every 3-4 weeks for six courses. The randomization incorporated stratification according to performance status and the amount of residual tumor (maximum diameter </=2 or >2 cm). Clinical assessment was performed with abdominal CT and serum CA-125. Responses were observed in 33/46 = 72% (95/CI 56.5-84.0) of the IV group and in 33/44 = 75% (95/CI 59.7-86.8) of the IP group with 48 and 45% clinical complete responses, respectively. Times to progression were 19 months (8-62+) for the IV group and 18 (6-72+) for the IP group. Median survivals were: 25 months (6-80+) and 26 months (6-72+), respectively. Significantly more patients in the IV group than in the IP group had grade 3 or higher leukopenia (p < 0. 01) and grade 3 thrombocytopenia (p < 0.09). Morbidity due to infectious complications in the IP group was minimal. It seems that IP CBP is equally effective to IV administration in terms of response and survival with less myelotoxicity. The favorable results on survival demonstrated in studies with IP C administration in patients with small volume disease [Alberts et al: N Engl J Med 1996;335:1950-1965] could not be repeated in the present study applying CBP in patients with variable tumor size and a relatively small number of patients. The likelihood that patients with large volume disease would benefit from a regional approach compared to systemic administration is small and this explains the inability to detect a difference between the two arms.