Cisplatin and carboplatin are platinum-based chemotherapeutic agents with broad antitumor activity and significantly different toxicity profiles. They are commonly used in combination with etoposide (VP-16) in chemotherapeutic regimens. We conducted a phase I trial using the combination of cisplatin, carboplatin, and etoposide in advanced malignancy, aimed at delivering a higher dose intensity of active platinum species while taking advantage of their nonoverlapping toxicities. Etoposide was added because of its synergistic action with platinum compounds. The initial chemotherapy regimen consisted of carboplatin 180 mg/m2 on day 1, cisplatin 70 mg/m2 on day 1, and etoposide 60 mg/m2 on days 1-3. Dose was escalated based on toxicity observed at each level and separately for patients with a previous history of chemotherapy and for those with no prior treatment. Thirty-six patients were entered in the study, and 33 were evaluable. Hematologic toxicity was dose limiting. Grade 3-4 leukopenia was noted in 22 of 33 (66%) patients and grade 3-4 thrombocytopenia was noted in 16 of 33 (48%). No serious bleeding complications occurred. There was one treatment-related death due to neutropenic sepsis. Nonhematologic toxicity was mild and not dose limiting. Ototoxicity and nephrotoxicity were minimal. No complete responses (CR) occurred. Nine of 33 (27%) patients had objective responses, including 3 patients with adenocarcinoma of the esophagus or gastroesophageal junction who had failed prior chemotherapy. Fifteen of 33 (45%) patients had stable disease. The maximum tolerated dose varied for patients who had received prior chemotherapy and for those who were previously untreated. For further studies, the recommended dosing for previously untreated patients is carboplatin 300 mg/m2 on day 1, cisplatin 70 mg/m2 on day 1, and etoposide 105 mg/m2 on days 1-3. The recommended dosing for patients with a history of prior chemotherapy is carboplatin 220 mg/m2 on day 1, cisplatin 70 mg/m2 on day 1, and etoposide 75 mg/m2 on days 1-3. The combination of cisplatin, carboplatin, and etoposide merits further testing in phase II trials.