Background: Theophylline is a dimethylxanthine that reduces oxidative stress. Zinc sulfate as a strong antioxidant commonly is prescribed in treatment of male subfertility. Therefore, this study aimed to investigate the effect of co-administration of theophylline and zinc sulfate on Total Antioxidant Capacity (TAC) and Malondialdehyde (MDA) Levels in Seminal Plasma of Asthenoteratozoospermic men. Methods: 120 asthenoteratozoospermic patients participated in a double-blind, randomized clinical trial study and were randomly divided into four groups: Placebo, theophylline, theophylline + zinc sulfate and zinc sulfate. After 3 months of oral administration, the TAC level was analyzed using the ferric- reducing ability of plasma assay (FRAP). The MDA level was also analyzed using Tiobarbiotic acid (TBA) method at the beginning and at the end of the of the trial. Data was analyzed statistically using the repeated measurements ANOVA and the means were considered significantly different at P<0.05. Results: The TAC level of seminal plasma increased significantly in all three groups compared to the placebo; but, this increase was significantly higher in the theophylline + zinc sulfate group than the theophylline and zinc sulfate groups. The MDA level of seminal plasma reduced significantly in all three groups compared to the placebo; but, this reduction was significantly higher in the theophylline + zinc sulfate group than the theophylline and zinc sulfate groups. The increase of TAC level and decrease of MDA level of seminal plasma was significantly higher in the zinc sulfate group than the theophylline group. There was no significant difference in the mean TAC and MDA of seminal plasma in the placebo group, before and after administration. Conclusion: Co-administration of theophylline and zinc sulfate, as two antioxidants, could reduce oxidative stress in seminal plasma. Because of the synergism of these drugs, this combination may be prescribed in the case of infertile men
