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The aim was to evaluate the association of molecular‐level human leukocyte antigen (HLA) mismatching with post‐transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984‐06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor‐recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody‐verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA‐DR AAMM load had inferior 1‐year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01–1.28). The HLA‐AB AAMM load showed no impact on graft survival. In the subgroup with available split‐level information, we observed an inferior graft survival for a higher HLA‐DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04–1.44) and a higher risk for rejection for an increasing HLA‐AB (HR, 1.70; 95% CI, 1.29–2.24) and HLA‐DR (HR, 1.32; 95% CI, 1.09–1.61) AAMM load. No impact on the development of CAV was found. Molecular‐level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.