The majority of JAK2^V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALR^MUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR^MUT-specific T cells are rare in patients with CALR^MUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR^MUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALR^MUT neoepitopes with high affinity are underrepresented in patients with CALR^MUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALR^MUT MPN would not efficiently respond to a CALR^MUT fragment cancer vaccine but would when immunized with a modified CALR^MUT heteroclitic peptide vaccine approach. We found that heteroclitic CALR^MUT peptides specifically designed for the MHC-I alleles of patients with CALR^MUT MPN efficiently elicited a CALR^MUT cross-reactive CD8⁺ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR^MUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8⁺ T cell response to the CALR^MUT fragment upon immunization with a CALR^MUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide–based cancer vaccines in patients with CALR^MUT MPN.