Background: Abnormal female immune response is one of the potential causes of unexplained infertility (UI). Seminal plasma (SP) is an important regulator of female immune responses during pregnancy. This study investigated a SP effect on the expression of CD4⁺ T-cell-related cytokines in a group of UI woman candidates for in vitro fertilization (IVF) and healthy fertile women. Materials and Methods: This was a semi-experimental study that performed on 20 UI couples (ten unsuccessful and ten successful IVF outcomes) and 10 fertile couples as the healthy group. CD4⁺ T-cells were separated from peripheral blood mononuclear cells of women by magnetic-activated cell sorting technique and incubated with (stimulated condition) or without (unstimulated condition) SP of their husbands. After incubation, real-time polymerase chain reaction method was used to investigate interleukin (IL)-23, IL-17, IL-4, IL-10, transforming growth factor (TGF)-β, and interferon (IFN)-γ gene expression. Mann–Whitney U-test, Kruskal–Wallis test, and Wilcoxon signed-rank test were used for statistical analysis. Results: Baseline TCD4⁺ mRNA levels of IL-23 (P = 0.03) and TGF-β (P = 0.01) were different between healthy and infertile groups. However, IL-17, IL-4, IFN-γ, and IL-10 were expressed similarly regardless of fertility status. Comparing mRNA expression before and after SP exposure, our results have shown that relative expression of IL-23 significantly increased in successful (P = 0.04) and unsuccessful IVF groups (P = 0.01), whereas IL-10 expression increased only in the IVF failure group (P = 0.01). Conclusion: SP can make a positive effect on IVF outcome through alteration in CD4+ T-cell-related cytokines expression, especially IL-10 and IL-23.