The anti-cancer immune response against mutated peptides of potential immunological relevance (neoantigens) is primarily attributed to MHC-I-restricted cytotoxic CD8+ T cell responses. MHC-II-restricted CD4+ T cells also drive anti-tumor responses, but their relation to neoantigen selection and tumor evolution has not been systematically studied. Modeling the potential of an individual’s MHC-II genotype to present 1,018 driver mutations in 5,942 tumors, we demonstrate that the MHC-II genotype constrains the mutational landscape during tumorigenesis in a manner complementary to MHC-I. Mutations poorly bound to MHC-II are positively selected during tumorigenesis, even more than mutations poorly bound to MHC-I. This emphasizes the importance of CD4+ T cells in anti-tumor immunity. In addition, we observed less inter-patient variation in mutation presentation for MHC-II than for MHC-I. These differences were reflected by age at diagnosis, which was correlated with presentation by MHC-I only. Collectively, our results emphasize the central role of MHC-II presentation in tumor evolution. Display omitted •Patient- and residue-specific PHBR-II score estimates mutation presentation by MHC-II•Tumors are less likely to harbor driver mutations that bind well to MHC-II•Frequent driver mutations are universally poorly presented by MHC-II•MHC-II shows less inter-patient variability but stronger selective effects than MHC-I Inter-individual variation in MHC-II genotype influences the evolution of patient-specific tumor mutational spectra, emphasizing the key role of CD4+ T cells in anti-tumor immunity.