The study investigated the association between EPAS1 and ATP6V1E2 gene polymorphisms and susceptibility to high-altitude polycythemia (HAPC) in a Chinese Tibetan population. It included 78 patients with HAPC and 85 healthy controls. Single nucleotide polymorphisms in the EPAS1 gene (rs1868092, rs4953396, rs4953354) and in ATP6V1E2 (rs896210) were analyzed. Using logistic regression analysis, multifactorial dimensionality reduction, protein-protein interaction and KEGG pathways, a significant association of these polymorphisms with HAPC risk was found. ATP6V1E2 rs896210 and EPAS1 rs1868092, rs4953396, rs4953354 polymorphisms were significantly associated with genetic susceptibility to HAPC. There were synergistic effects between these genetic loci. The results provide evidence for the genetic mechanism of diseases adapted to high altitude and are useful for individualized risk assessment and potential therapeutic targets.