HLA class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, multifaceted HCMV-encoded immunoevasins target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied. While US10 has been shown to interfere with HLA-G expression, its ability to block classical HLA-I antigen presentation remains unknown. In this study, we demonstrate that US10 recognizes and binds to all HLA-I (HLA-A,-B,-C,-E,-G) heavy chains. Additionally, impaired recruitment of HLA-I to the peptide loading complex was observed. Notably, the associated effects varied significantly dependent on HLA-I genotype and allotype: i) HLA-A molecules evaded down-regulation by US10, ii) tapasin-dependent HLA-B molecules showed impaired maturation and cell surface expression, iii) β2m-assembled HLA-C, in particular HLA-C*05:01 and -C*12:03, and HLA-G were strongly retained in complex with US10 in the endoplasmic reticulum. These genotype-specific effects on HLA-I were confirmed through unbiased HLA-I ligandome analysis. Thus, the US10-mediated impact on HLA-I results in geno- and allotypic differences in a so far unparalleled and multimodal manner.