Background: Neoantigen vaccines can activate T-cells that specifically kill tumor cells. However, most vaccine peptides, selected either as HLA-binders or as HLA-presented epitopes, do not induce T-cell responses in HLA allele-matched individuals. We hypothesized that personal-epitopes (PEPIs) binding to multiple autologous HLA-alleles induce potent T-cell responses. Methods: Epitopes binding to single HLA and PEPIs binding to 3 autologous HLA-alleles were identified with our novel and validated PEPI Test (CE Marked) and correlated with CD8+ and CD4+ T-cell responses of (pre)malignant patients vaccinated with Synthetic Long Peptides (SLPs) in 2 clinical trials. A Model Population of 433 HLA-genotyped individuals was used to determine the percentage of subjects with PEPIs from SLPs (PEPI-Score). As a proof of principle, a personal vaccine was developed matching with 14 HLA-alleles of a cancer patient with PEPIs from 12 tumor-antigens. T-cell reactivities were tested by interferon-γ ELISPOT. Results: There was no correlation between single HLA-binding epitopes and HPV-specific T-cell responses of patients. In contrast, there was 90% and 69% agreement between HLA-class-I PEPIs and CD8+ T-cell responses (p < 0.001) and HLA-class-II PEPIs and CD4+ T-cell responses (p = 0.005), respectively. PEPI-Score predicted the T-cell response rate of SLP vaccine clinical trials. As predicted by the PEPI Test, personal vaccine treatment activated tumor-specific T-cells: 91% and 100% of the vaccine peptides elicited CD8+ and CD4+ T-cell responses, respectively. Conclusions: A patient’s HLA genotype is a major determinant of vaccine responses and PEPIs are genetic biomarkers of T-cell responses. PEPI Test prediction of vaccine responses can be utilized by clinicians for selecting the vaccine treatment and for the development of highly immunogenic personal vaccines matched to a patient’s complete HLA genotype (NCT03391232).