Introduction. Medications such as antioxidants and recombinant FSH are prescribed to improve sperm DFI (DNA fragmentation index) and treat infertility. Due to the high cost and duration of medications, in this study, we decided to investigate the effectiveness of combining these two medications with lower doses and in less time, compared to previous studies prescribing them individually, to reduce sperm DFI in infertile men. Methods. This study, a retrospective observational before and after trial, included a group ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M1"> <mi>n</mi> <mo>=</mo> <mn>94</mn> </math> ) of men aged 18-50 years with <math xmlns="http://www.w3.org/1998/Math/MathML" id="M2"> <mtext>DFI</mtext> <mo>></mo> <mn>20</mn> <mi>%</mi> </math> suffering from male factor infertility in an andrology clinic in Tehran, Iran, from 2019 to 2020. Patients received the combination of two medications, recombinant FSH every 5 days (75 IU subcutaneously) and an antioxidant every day (selenium, vitamin E, CoQ10, and folic acid) for 2 months. The patient’s sperm DFI and sperm parameters have been measured before and after the medication and were reported in patient’s files. In all patients, we compare the sperm DFI and sperm parameters before and after the treatment to evaluate the effect of the combination therapy. Results. The sperm DFI was significantly reduced ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M3"> <mi>p</mi> </math> value ≤0.001) in the patients treated by the combined medication. The sperm DFI improvement was 50.16% in the total population. However, there were no significant changes in other sperm parameters such as sperm concentration, total motility, progressive motility, immotile sperms, and abnormal morphology. Total sperm count and nonprogressive motility had significant changes statistically. Conclusion. Sperm DFI is an important indicator for evaluating the quality of semen. In this study, we demonstrate that the combination of recombinant FSH and antioxidants in a shorter time and with lower doses is effective in reducing DFI significantly. But in terms of other sperm parameters, it does not make a significant difference.