Phase II trials of second-line intraperitoneal (IP) cisplatin-based therapy in patients with ovarian cancer have demonstrated the ability of this approach to produce objective antitumor responses, including surgically defined complete responses (CRs), in individuals with persistent small-volume disease after front-line cisplatin-based intravenous (IV) treatment. To examine the influence of a prior response to systemic cisplatin on the activity of second-line IP cisplatin, we retrospectively analyzed two phase II trials of cisplatin-based IP therapy in persistent/recurrent ovarian cancer conducted at our institution. Of the 89 assessable patients on the two trials, 52 (58%) had previously responded to IV cisplatin. The overall response and CR rates to second-line IP cisplatin-based therapy in this previously responding population were 56% and 33%, respectively, compared with overall response and CR rates in the 37 nonresponders to IV cisplatin of 11% and 3%, respectively (P less than .001; chi 2, 1 df). In the 36 patients responding to systemic cisplatin and whose largest tumor mass measured less than 1 cm at IP cisplatin initiation, a 42% CR rate was observed, compared with a 7% CR rate in the 14 patients with the same bulk of disease who had previously failed to respond to systemic cisplatin (P less than .025). We conclude that a prior response to systemic cisplatin strongly influences the antineoplastic activity of second-line IP cisplatin in ovarian cancer.