Clinical trials in urothelial cancer exclude a large population of patients. An observational study evaluated the behavior of frail patients not eligible for cisplatin- or carboplatin-based regimens. Urothelial cancer patients requiring chemotherapy with either chronic renal failure (creatinine clearance <60 ml/min), and/or performance status (PS) > or =2 and/or cardiac dysfunction were prospectively observed. The treatment associated gemcitabine 1200 mg/m and oxaliplatin 85 mg/m, bimonthly (GO). Over 2 years, 31 of 45 (69%) patients with urothelial cancer requiring chemotherapy were not eligible for cisplatin- or carboplatin-based chemotherapy. Sixteen (52%) had a PS > or =2, 23 (74%) had creatinine clearance <60 ml/min, and 20 (65%) had an underlying cardiopathy. A total of 178 cycles of GO were administered (median 6 per patient, range 2-12). No aggravation of renal or cardiac status was noted. Acute grade 3 and 4 neutropenia and thrombocytopenia were observed in 16 and 13% of patients, respectively, with one febrile neutropenia. The median progression-free and overall survival values were 4.2 and 9.5 months, respectively. The majority of urothelial cancer patients have severe renal or cardiac comorbidities, and we conclude that in this subset of patients the combination of gemcitabine and oxaliplatin is well tolerated, and its clinical activity warrants further evaluation.