Background: Theophylline acts as a cyclic-AMP phosphodiesterase inhibitor which elevates cAMP dependent sperm capacitation, however it can also damage sperm DNA integrity and change the proteins expression. Moreover, Zinc sulfate as an antioxidant can prevent sperm DNA damages. Objective: We investigated the effect of co-administration of theophylline and zinc sulfate on Bcl-2, Bax and Caspase-3 proteins expression and DNA integrity in infertile men with asthenoteratozoospermia. Methods: 120 asthenoteratozoospermic patients participated in a double-blind, randomized clinical trial study and were randomly divided into four groups: Placebo, theophylline (200 mg/day), theophylline (200 mg/day) +zinc sulfate (220 mg/day) and zinc sulfate (220 mg/day). After 3 months of Oral treatment, the expression of proteins was analyzed using western blotting and the DNA fragmentation was also analyzed using sperm chromatin dispersion test at the beginning of the trial and at the end of the treatment. Data was analyzed statistically using the repeated measurements ANOVA and the means were considered significantly different at P<0.05. Results: The expression of Bax and caspase-3 proteins increased significantly in the theophylline received group, while it showed a significant reduction in the zinc sulfate received group compared to the placebo. The expression of Bcl-2 protein increased significantly in the zinc sulfate received group, while it showed a significant reduction in the theophylline received group compared to the placebo. Sperm DNA fragmentation increased significantly in the theophylline received group, while it showed a significant reduction in the zinc sulfate received group compared to the placebo. There was no significant difference in the expression levels of Bcl-2, Bax and caspas-3 proteins and the mean sperm DNA fragmentation in the theophylline+zinc sulfate group compared to the placebo. Conclusion: Co-administration of theophylline and zinc sulfate, as an antioxi
