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Objective: To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and nonobstructive azoospermia (NOA) susceptibility.Design: MHC region fine-mapping analysis based on previous NOA genome-wide association study (GWAS) data.Setting: Medical university.Patient(s): Nine hundred and eighty-one men with NOA and 1,657 normal fertile male controls.Intervention(s): None.Main Outcome Measure(s): The MHC region imputation assessed with SNP2HLA software, taking the specific Han-MHC database as a reference panel; statistical significance of the MHC variants calculated using logistic regression models; functional annotation based on online public databases; and phenotypic variances explained by specific groups of genetic variants estimated using the fixed effects model from individual associations.Result(s): Two independent risk loci, rs7194 (odds ratio [OR] 1.37) at MHC class II molecules and rs4997052 (OR 1.30) at MHC class I molecules, were identified. Functional annotation showed rs7194 may tag the effect of multiple amino acid residues and the expression of HLA-DQB1 and HLA-DRB1; while rs4997052 showed the effect of amino acid changes of HLA-B at position 116 as well as the expression of HLA-B and CCHCR1, which coexpressed with genes enriched in pathways of spermatogenesis and male gamete generation. The novel variant rs4997052 identified in our study can explain another approximately 0.66% of the phenotypic variances of NOA.Conclusion(s): We fine-mapped the MHC region and identified two loci that independently drove NOA susceptibility. These results provide a deeper understanding of the association mechanisms of MHC and NOA risk. [ABSTRACT FROM AUTHOR]