Proton-pump inhibitors (PPIs) are among the most widely used drugs worldwide.PPI use has recently been linked to adverse changes in semen quality in healthy men;however,the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility.We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men.We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013.Patients who reported using any PPIs for ＞3 months before semen sample collection were included;7698 subfertile men taking no medication served as controls.Data were gathered on patient age,medication use,and conventional semen parameters;patients taking any known spermatotoxic medication were excluded.Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age.A total of 248 patients (258 samples) used PPIs for at least 3 months before semen collection.In regression models,PPI use (either as the only medication or when used in combination with other nonspermatotoxic medications) was not associated with statistically significant changes in semen parameters.To our knowledge,this is the largest study to compare PPI use with semen parameters in subfertile men.Using PPIs was not associated with detrimental effects on semen quality in this retrospective study.