Abstract Introduction The goal of treatment for infertile men with testosterone deficiency is to improve intratesticular androgen levels with the aim of increasing the last step of maturation in spermatogenesis. Medical therapy for male factor infertility remains largely empiric and relies on off-label use of medications known to increase intratesticular testosterone levels, such as selective estrogen receptor modulators (clomiphene citrate and enclomiphene citrate) and gonadotropins (human chorionic gonadotropin). There is scarce data of whether the above-mentioned treatment options offer different success rates in improving testosterone levels and sperm parameters. Objective To compare the improvement in total testosterone, intratesticular testosterone, and sperm parameters between patients receiving medical treatment with clomiphene citrate (CC), enclomiphene citrate (ECC), or clomiphene citrate + human chorionic gonadotropin (HCG). Methods We conducted a retrospective study from 2018 to 2022 of men with primary infertility, testicular deficiency, and secondary hypogonadism receiving ECC, CC or CC+HCG for at least 3 months. Among the different treatment groups, we assessed baseline and follow-up total testosterone, 17-hydroxyprogesterone (17-OH), semen parameter(s), and demographics. Semen quality improvement was based on assisted reproduction eligibility according to the total motile sperm count (TMSC) value: in-vitro fertilization ( 9 million). Intratesticular testosterone upgrading was based on 17-OH level, with expected values being ≥55 ng/dL. Variables were compared using paired t-test and ANOVA. Results A total of 18 men received ECC, 19 received CC and 9 received CC+HCG. Mean age was 41.1±2.28 years in the ECC group, 40.62±1.17 in the CC group, and 45±2.75 in the CC+HCG group (p=0.458). Overall, the mean follow-up was 3.64 ±2.14 months (p=0.242). The 3 treatment groups exhibited a statistically significant increase in total testosterone (table 1), but only the CC and CC+HCG groups had a statistically significant improvement in the level of 17-OH (p 9 million. Conclusions Our study showed that ECC, CC and CC+HCG are effective treatment regimens for improving total testosterone without negatively affecting spermatogenesis. Nonetheless, their effects on intratesticular testosterone and sperm parameters varied, suggesting that choosing the best treatment option for improving sperm parameters should be an individualized patient decision. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Acerus, Boston Scientific, Endo Pharmaceuticals and Coloplast.