The fact that urothelial carcinomas (UC) often contain areas with different histologic grades has been recently shown to bear some prognostic relevance. Here we examined the prognostic significance of a grading system considering tumor heterogeneity in muscle-invasive bladder carcinomas. 151 UC treated by radical cystectomy were included. According to the World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification, histologic grade was low-grade (LG) in 8 and high-grade (HG) in 143 cases. 65 HG tumors which focally harbored LG areas were assigned to mixed-type (MT) carcinomas. Mean follow-up was 50 months. While the WHO/ISUP classification showed no significant correlation with disease-specific survival (p = 0.3995 by log-rank test), stratification into LG/MT and HG tumors had a significant prognostic relevance (p = 0.0404). Nodal status was identified as the only independent prognostic factor (p = 0.0001 by multivariate analysis). In this respect, stratification into LG/MT and HG tumors missed the level of statistical significance by a norrow margin (p = 0.07 by multivariate analysis), but it turned out better than tumor category (p = 0.08). In conclusion, a grading system considering tumor heterogeneity may improve the predictive power of the WHO/ISUP classification in muscle-invasive UC of the urinary bladder. Although the two-tired grading system proposed in this study was not identified as an independent prognostic factor, it may help to obtain additional prognostic information on patients with advanced bladder cancer treated by radical cystectomy.