Objective AZFc deletions cause significant phenotypic heterogeneity with respect to spermatogenesis; however, the reason for this is poorly understood.Recently, TSPY1 copy number variation (CNV) was determined to be a potential genetic modifier of spermatogenesis.We performed a large-scale cohort study to investigate the effect of TSPY1 CNV on spermatogenesis and to elucidate the possible contribution of TSPY1 genetic variation to the phenotypic expression of AZFc deletions.Methods Haplogrouping of the Y-chromosome and quantification of the TSPY1 copy number were performed in 2,272 Han Chinese males with different spermatogenic statuses (704 males with the b2/b4 or gr/gr deletion, and 1,568 nonAZFc-deleted males).Results Our data revealed that the TSPY1 copy number distributions were significantly different among non-AZFc-deleted males with different spermatogenic phenotypes.Lower sperm production and an elevated risk of spermatogenic failure were observed in males with fewer than 21 TSPY1 copies and in those with more than 55 copies relative to men with 21-35 copies.Similar results were observed in males with the gr/gr deletion.Conclusions These findings indicate that TSPY1 CNV affects an individuals susceptibility to spermatogenic failure by modulating the efficiency of spermatogenesis and strongly suggest that there is a significant quantity effect of TSPY1 copy number on the phenotypic expression of the gr/gr deletion.To our knowledge, this CNV is the first independent genetic factor that has been clearly observed to influence the spermatogenic status of gr/gr-deletion carriers.A combined genetic analysis of TSPY1 copy number and the gr/gr deletion could inform the clinical counseling of infertile couples.(Hum Mol Genet, 2013 Jan 18.