Surgery is considered the most common choice for the treatment of male infertility with clinical varicocele. Increased numbers of mast cells (MCs) have been associated with different types of infertility, including varicocele. Despite there being different reports on improved fertility following administration of MC blockers, there is no report on the effect of a MC blocker on varicocele or after varicocelectomy. Therefore, the aim of this study was to evaluate the effect of Zaditen on semen quality, protamine content, DNA damage and fertility post-surgery. The study included 103 infertile men who were referred to Isfahan Fertility and Infertility Center for varicocelectomy. Varicocele individuals were randomly divided into control (52) and treatment groups (51). Semen parameters, WBC/mL, protamine content (chromomycin A3 staining) and DNA integrity (sperm chromatin dispersion test) were assessed before and 3 months after surgery. Comparison of the aforesaid parameters between the two groups revealed significant improvement in the treatment group compared with the control group, with the exception of DNA integrity. In addition, the cumulative pregnancy significantly improved by 9 months post-surgery in the treatment group (41.17%) compared with the control group (21.15%). The results of this study, for the first time, reveal that MC blockers such as Zaditen improve semen parameters, chromatin integrity and pregnancy rates when administered as adjunct therapy post-varicocelectomy.