Pentoxifylline is a derivative of methylxanthine that affects sperm motility. Also, zinc is an antioxidant that is involved in the activation of antioxidant enzymes. This study aimed to evaluate the effect of co-administration of pentoxifylline, and zinc in men with idiopathic infertility. In the present study, men with idiopathic infertility were identified and randomly divided into four groups: pentoxifylline, zinc, pentoxifylline + zinc, and placebo. According to the grouping, the patients received pentoxifylline and zinc for 3 months. Then, sperm parameters, biochemical factors, reproductive hormones, inflammatory factors, and DNA damage were evaluated before and after intervention. Data analysis was performed using SPSS software. Pentoxifylline and zinc were significantly effective in improving biochemical parameters, inflammatory factors, concentration, and motility of sperm. Pentoxifylline did not affect sperm morphology and reproductive hormones. However, in the zinc and zinc + pentoxifylline groups, a significant increase in normal morphology and reproductive hormones was observed. In the pentoxifylline group, sperm DNA fragmentation increased significantly, while in the zinc and zinc + pentoxifylline group, DNA fragmentation reduced significantly. Because of the role of zinc in protecting sperm chromatin, it is recommended that zinc and pentoxifyllinebe prescribed simultaneously. Clinical trial code: NCT05156684.