Twenty-one patients with advanced ovarian cancer proven resistant to standard alkylating chemotherapy were evaluated in a prospective study of Hexamethylmelamine. All but three patients received 8 mg/kg daily with dose modifications appropriate to the degree of toxicity; the latter three patients were treated on an intermittent 14 day course of 8 mg/kg daily. Six patients (28%) experienced an objective response with a median duration of 2.5 months (range 1--5 months). The toxic effects requiring dose modification were gastrointestinal in 57%, hematologic in 62%, and neurologic in 28.5%. An average of 60.5% of the total projected dose was tolerated for a median of 44 days (range 7--113). Twelve patients (57%) experienced severe toxicity requiring discontinuation of therapy. It is apparent from this study that Hexamethylmelamine is an active agent in ovarian cancer and is not invariably cross-resistant to conventional alkylating agent therapy. These two characteristics make it an attractive agent for use in combination. Its toxicity in previously treated patients in the schedules used here, however, is substantial.