AbstractImprovement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.