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Abstract Background Antiepileptic drugs are responsible for reproductive dysfunction in male epileptic patients. Objectives To evaluate the effect of valproate (VPA) versus levetiracetam (LEV) as a monotherapy on males’ sex hormones and sperm parameters in newly diagnosed epileptic patients. Materials and methods This comparative study included 50 newly diagnosed epileptic male patients. All patients were subjected to complete general and neurological examination, Doppler ultrasonography of the testis, pre- and post-treatment serum sex hormone assay, and semen analysis. Post-treatment re-evaluation checkpoint was determined if 8 weeks have passed after the last seizures. This study included two groups, group I (25 patients were treated by VPA) and group II (25 patients were treated by LEV). Results There was no statistical difference between groups regarding their baseline characteristics. In group I, at post-treatment checkpoint, we found significant decrease in luteinizing hormone and follicle-stimulating hormones and highly significant increase of prolactin serum level. In sperm parameters, there was significant decrease of all measured items. In group II, serum sex hormone was not significantly changed at post-treatment checkpoint but semen analysis parameters were significantly decreased regarding all items. In comparison between the two groups, there was significant decrease of sperm concentration among group II with highly significant decrease of normal morphology of sperm among group I. Conclusion Both VPA and LEV had adverse effects on the semen of male epileptic patients while VPA had also an adverse effect on sex hormones.