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STUDY QUESTION What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment? SUMMARY ANSWER The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment. WHAT IS KNOWN ALREADY The roles of Y chromosomal genetic background in spermatogenesis are controversial and vary among human populations. Individuals in predisposed Y-hgs may carry some genetic factors, which might be a potential genetic modifier for the Y-hg-specific susceptibility to spermatogenic impairment. STUDY DESIGN, SIZE, DURATION A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a two-stage association study to investigate the risk and/or protective Y-hgs for spermatogenic impairment. In addition, the genetic causes for the predisposition of certain Y-hg to spermatogenic impairment were investigated. Deletion typing and DAZ gene copy number quantification were performed for individuals in predisposed Y-hgs. MAIN RESULTS AND THE ROLE OF CHANCE Y-hgs K* and O3e* showed significantly different distribution between cases and controls consistently in two-stage studies. Combined analyses identified significant predisposition to non-obstructive azoospermia in Y-hg K* [odds ratio (OR) 8.58; 95% confidence interval (CI) 3.31–22.28; P = 1.40 × 10−5], but a protecting effect in Y-hg O3e* (OR 0.64; 95% CI 0.53–0.78; P = 4.20 × 10−5). Based on the dynamic nature of the Y chromosome, we hypothesized that Y-hgs K* and O3e* may be accompanied by modifying genetic factors for their predisposing or protecting effects in spermatogenesis. Accordingly, we quantified the multi-copy DAZ gene, which has variable copy numbers between individuals and plays an important role in spermatogenesis. In combined analysis, we found that the over-dosage of DAZ was significantly more frequent in Y-hg K* than in O3e* (OR 4.79; 95% CI 1.67–13.70; P = 6 × 10−3). LIMITATIONS, REASONS FOR CAUTION Owing to the inconsistency of genetic background, it remains to be determined whether the results derived from Han Chinese populations are applicable to other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study can advance the etiology of spermatogenic impairment, and also shed new light on Y chromosome evolution in human populations. Y-hg-specific genetic factors of modifying spermatogenic phenotypes deserve further investigation in larger and diverse populations. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by grants from National 973 Program (2009|CB941703, 2011CB944304 and 2012CB944600), National Natural Science Foundation of China (30930079, 81100461 and 31000552), Jiangsu Natural Science Foundation (BK2011774), Research Fund for the Doctoral Program of Higher Education of China (RFDP) (20113234120001), University Natural Science Research Project in Jiangsu Province (11KJB330001) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). There were no competing interests. [ABSTRACT FROM PUBLISHER]