Background: Pemetrexed has demonstrated a favorable response with minimal toxicity when used as single agent as first-line and second-line treatment for advanced urothelial carcinoma. The safety and tolerability of pemetrexed plus cisplatin combination has been widely recognized in malignant mesothelioma. This trial was performed to evaluate the efficacy and safety of pemetrexed plus cisplatin in advanced urothelial carcinoma. Methods: Eligible criteria included chemotherapy-naïve advanced urothelial carcinoma, ECOG PS 0-2 and measurable disease. Pemetrexed 500mg/m² on day 1 with cisplatin 70 mg/m²on day 1 were administered every 3 weeks til disease progression or a maximal of 8 cycles. Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicities. Response was evaluated every 6 weeks according to the RECIST criteria v.1.0 and toxicities were assessed with NCI CTCAE v.3.0. Results: A total of 42 patients were enrolled and 2 patients were excluded because of different histology and concomitant malignancy. At the time of this analysis, 36 patients (median age 66 years, ECOG 0-1 100%, visceral metastasis 50.0%, recurrent disease 61.1%) were evaluable; 6 patients were too early to assess. Twenty four partial responses for an overall response rate of 66.7% [95% confidence interval (CI) 50.3-79.9%] were documented. Six patients had stable disease. The median PFS was estimated to be 6.9 months [95% CI 6.2-7.7 months]. The median OS was 16.3 months [95% CI 12.9-19.7 months]. The most common grade 3 or 4 toxicities were neutropenia in 33.3% of patients. No one experienced febrile neutropenia. Other grade 3 or 4 hematological and non-hematological toxicities were rarely observed (thrombocytopenia 6%, anemia 6%, transaminitis 6%, nausea 3%, anorexia 3%, edema 3%, dyspnea 3%). Conclusions: The combination of pemetrexed and cisplatin is very active, with an overall response rate of 66.7% and well tolerated in patients with advanced urothelial cancer. The final mature results will be presented in the meeting. Clinical trial information: NCT01490437.