Cytarabine and hydroxyurea in combination are known to inhibit the DNA excision repair system. Given this system is responsible for repair of cisplatin-DNA adducts, we hypothesized that combining cytarabine, hydroxyurea, and cisplatin in an appropriate schedule might inhibit adduct repair, increase the number of DNA lesions, and produce synergistic cell kill. In vitro experiments using clinically achievable doses and schedules of these antimetabolites demonstrated cytotoxic synergy with the three-drug combination, but little or no such synergy with either antimetabolite plus cisplatin. The inclusion of hydroxyurea was necessary to achieve maximum synergy. Increased levels and persistence of cisplatin-induced DNA interstrand cross-links were observed, suggesting repair inhibition may have occurred. The dose of cisplatin required to inhibit colony formation by 90% was reduced approximately one third, even after normalization for the cytotoxic component(s) of hydroxyurea, cytarabine, and hydroxyurea plus cytarabine. Using one of the two optimal in vitro schedules for the three-drug combination, we performed a clinical pilot study in two patient cohorts (with and without prior systemic therapy). Administration of the program was feasible, and resulted in dose-limiting thrombocytopenia only in the cohort with prior chemotherapy. Azotemia was treatment-limiting in responding patients. Responses were observed in patients with a variety of solid tumors, including several patients who had previously failed cisplatin therapy. Modifications of this program are discussed, which have, to date, significantly decreased the toxicity concerns raised by the first trial. Phase II trials are planned in patients with a variety of cisplatin-responsive and nonresponsive neoplasms.