Background: Varicocele is the most common correctable cause of male infertility. The treatment of varicocele is surgery. However, which patients will benefit from the surgery is controversial. Our aims to investigate the effect of systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) on varicocelectomy success. Methods: Patients who underwent varicocelectomy in our clinic between January 2016 and June 2022 were analyzed retrospectively. Varicocelectomy success was defined as >50% increase in post-operative total motile sperm count (TMSC) in those with pre- operative TMSC > 5 million and at least 100% increase in those with <5 million. The patients were divided into two groups as benefiting from the treatment (Group 1) and no benefits (Group 2). Results: Of the 207 patients who underwent varicocelectomy, 144 (69.6%) of them improved their semen parameters, and 63 (30.4%) did not. The optimum cut-off value of SII was 334.6, with an AUC of 0.733 (95% CI: 0.665–0.813). The best cut-off value for SIRI of 0.882, with an AUC of 0.692 (95% CI: 0.607–0.772). The highest sensitivity and specificity were 0.692 and 0.601 ( p < 0.001). In the multivariate analysis, only SII (OR: 3.152, 95% CI: 1.316–7.358; p = 0.003) and SIRI (OR: 2.919, 95% CI: 1.472–5.774; p = 0.002) were independent predictive factors for varicocelectomy success. Conclusions: Our results showed that preoperative SII and SIRI values were lower in infertile patients who underwent successful varicocelectomy. Therefore, we think that these parameters will be useful in identifying patients who will benefit before varicocelectomy.