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OBJECTIVE To conduct a phase II trial to determine the efficacy of cisplatin, a fixed dose-rate infusion of gemcitabine and gefitinib (an orally active epidermal growth factor receptor tyrosine kinase inhibitor) in patients with advanced urothelial carcinoma. PATIENTS AND METHODS Eligible patients had previously untreated measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2 and creatinine clearance of >50 mL/min. The treatment regimen consisted of cisplatin 70 mg/m2 on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, administered at a fixed dose rate of 10 mg/m2/min, given every 3 weeks concurrent with gefitinib 500 mg/day orally for a maximum of six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS In all, 27 patients were accrued before the study was halted because the dose-limiting toxicity (DLT) exceeded pre-established stopping rules. The DLT events were two grade 5 (one infection, one cardiovascular accident) and three with grade 4 non-haematological toxicity. In 25 evaluable patients there were nine objective responses, for an overall response rate of 36% (95% confidence interval, CI, 18–57%). The median (95% CI) survival time was 11.1 (5.2–35.3) months. CONCLUSION The combination of cisplatin, fixed dose-rate gemcitabine and gefitinib is active in advanced TCC, although the relative contribution of gefitinib cannot be determined. However, this regimen was associated with excessive toxicity. [ABSTRACT FROM AUTHOR]