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Study Question: Is there an association between sperm DNA methylation profiles and asthenozoospermia?Summary Answer: DNA methylation, at specific CpGs but not at the global level, was significantly different between low motile sperm cells of asthenozoospermic individuals and high motile sperm cells of normozoospermic controls.What Is Known Already: Aberrant DNA methylation, both globally and restricted to a specific gene locus, has been associated with male infertility and abnormal semen parameters.Study Design, Size, Duration: This was a case-control study investigating the differences in DNA methylation at CpGs in promoter regions between high and low motile sperm cells from eight normozoospermic controls and seven asthenozoospermic patients.Participants/materials, Setting, Methods: The liquid hybridization capture-based bisulfite sequencing method was used to determine DNA methylation at CpGs in promoter regions. The global inter-individual and intra-individual methylation variability were estimated by evaluating the methylation variance between and within different motile sperm fractions from the same or different individuals. Asthenozoospermia-associated differentially methylated or variable CpGs and differentially methylated regions were identified by comparing the DNA methylation of high motile sperm cells from normozoospermic controls with that of low motile sperm cells from asthenozoospermic patients.Main Results and the Role Of Chance: In this study, we determined the global DNA methylation level (24.7%), inter-individual variance (14.4%) and intra-individual differences between high and low motile sperm fractions (3.9%). We demonstrated that there were no statistically significant differences in either the global DNA methylation level or global methylation variability between sperm from men with normozoospermia or asthenozoospermia. Between high motile sperm from men with normozoospermia and low motile sperm from men with asthenozoospermia, we identified 134 differentially methylated CpGs, 41 differentially methylated regions and 134 differentially variable CpGs. The genomic distribution patterns of the differential methylation spectrum suggested that gene expression may be affected in low motile sperm cells of asthenozoospermic patients. Finally, through a functional analysis, we detected 16 differentially methylated or variable genes that are required for spermatogenesis and sperm motility or dominantly expressed in testis.Limitations, Reasons For Caution: The sample size in this study was limited, although the participants in the two groups were carefully selected and well matched. Our results must be verified in larger cohorts with the use of different techniques. Furthermore, our results were descriptive, and follow-up studies will be needed to elucidate the effect of differential methylation profiles on asthenozoospermia.Wider Implications Of the Findings: Our study identified asthenozoospermia-associated DNA methylation profiles and proposed a list of genes, which were suggested to be involved in the regulation of sperm motility through an alteration of DNA methylation. These results will provide promising clues for understanding the effect of DNA methylation on sperm motility and asthenozoospermia.Study Funding/competing Interests: This study was funded primarily by the National Natural Science Foundation of China, Shenzhen Project of Science and Technology and the National Basic Research Program of China. The authors have no competing interests. [ABSTRACT FROM AUTHOR]