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Fibroblast growth factor receptor 3 (FGFR3) mutations were recently found at a high frequency in well-differentiated urothelial cell carcinoma (UCC). We investigated the relationship between FGFR3 status and three molecular markers (MIB-1, P53 and P27kip1) associated with worse prognosis and determined the reproducibility of pathological grade and molecular variables. In this multi-center study, we included 286 patients with primary (first diagnosis) UCC. The histological slides were reviewed. FGFR3 status was examined by PCR-SSCP and sequencing. Expression levels of MIB-1, P53 and P27kip1 were determined by immunohistochemistry. Mean follow-up was 5.5 years (range, 0.4-18.4 years). FGFR3 mutations were detected in 172/286 (60%) of UCCs. G1-tumors had a FGFR3 mutation in 88% of cases, G3-tumors in 16%. Conversely, aberrant expression patterns of MIB-1, P53 and P27kip1 were seen in 5%, 2% and 3% of G1-tumors and in 85%, 60% and 56% of G3-tumors, respectively. In multivariate analysis with recurrence rate, progression and disease specific survival as endpoints, the combination of FGFR3 and MIB-1 proved of independent significance in all three cases. Using these two molecular markers, three molecular grades (mG) could be identified: mG1 (mutation; normal expression), favorable prognosis; mG2 (two remaining combinations), intermediate prognosis; mG3 (no mutation; high expression), poor prognosis. The molecular variables were more reproducible than pathological grade (85-100% vs. 47-61%). The FGFR3 mutation represents the favorable molecular pathway of UCC. Molecular grading provides a new, simple and highly reproducible tool for clinical decision making in UCC patients.