The fact that urothelial carcinomas (UC)often contain areas with different histologicgrades has been recently shown to bear someprognostic relevance. Here we examined theprognostic significance of a grading systemconsidering tumor heterogeneity inmuscle-invasive bladder carcinomas.151 UC treated by radical cystectomy wereincluded. According to the World HealthOrganization/International Society ofUrological Pathology (WHO/ISUP) classification,histologic grade was low-grade (LG) in 8 andhigh-grade (HG) in 143 cases. 65 HG tumorswhich focally harbored LG areas were assignedto mixed-type (MT) carcinomas. Mean follow-upwas 50 months.While the WHO/ISUP classification showedno significant correlation withdisease-specific survival (p = 0.3995 bylog-rank test), stratification into LG/MT andHG tumors had a significant prognosticrelevance (p = 0.0404). Nodal status wasidentified as the only independent prognosticfactor (p = 0.0001 by multivariate analysis).In this respect, stratification into LG/MT andHG tumors missed the level of statisticalsignificance by a norrow margin (p = 0.07 bymultivariate analysis), but it turned outbetter than tumor category (p = 0.08).In conclusion, a grading systemconsidering tumor heterogeneity may improve thepredictive power of the WHO/ISUP classificationin muscle-invasive UC of the urinary bladder.Although the two-tired grading system proposedin this study was not identified as anindependent prognostic factor, it may help toobtain additional prognostic information onpatients with advanced bladder cancer treatedby radical cystectomy.