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Varicocele (VC) is widely recognized as a prevalent etiological factor contributing to male infertility. It has been established that the generation of reactive oxygen species (ROS) plays a significant role in the progression and development of VC. Antioxidants may regulate ROS levels in these patients. Astaxanthin (ASX) is a carotenoid compound with notable antioxidant and anti-inflammatory characteristics. The current study postulated that the administration of ASX following varicocelectomy (VCT) could potentially enhance antioxidant status and semen quality in these patients. A total of 40 infertile males with clinical VC and abnormal semen analyses were randomly assigned to take part in the current trial. For 3 months following surgery, the intervention group took ASX (6 mg/day) while the control group received a placebo. After intervention, semen parameters, antioxidant status, and pro-inflammatory cytokines were compared between the two groups. Regarding semen parameters, antioxidant treatment led to a significant improvement in total and progressive motility in the treatment group ( p  < 0.05). Additionally, ASX led to a considerable increase in the expression levels of NRF2, Keap1, SOD2, SOD3, and BCL2, though the enhancement in the expression level of SOD3 was not statistically significant ( p  > .05). However, ASX significantly decreased the BAX expression level ( p  < .05). Even though the level of total antioxidant capacity (TAC) of seminal fluid (SF) increased significantly in the treatment group ( p  < .05), the level of total oxidative stress (TOS) in SF did not differ substantially between treatment and control groups ( p  > .05). Based on inflammatory factors in SF, ASX led to a considerable reduction in levels of TNF-α, IL-1β, and IL-6 ( p  < .05). Our findings demonstrated that ASX treatment provides an important contribution to VCT outcomes by modulating antioxidant status and pro-inflammatory cytokines. Our results indicated that ASX may be beneficial as an adjuvant therapy for infertile men following VCT., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)