Background <p>Adnexal involvement in endometrial cancer is traditionally regarded as an anatomical spread pattern within FIGO stage IIIA; however, its biological heterogeneity remains incompletely understood. The 2023 FIGO staging system distinguishes between favorable “synchronous” ovarian involvement (stage IA3) and true metastatic spread to the ovary (stage IIIA1), highlighting the biological heterogeneity of adnexal involvement. This study aimed to investigate the association between immunohistochemistry (IHC)-based molecular subtypes and adnexal involvement, together with relevant clinicopathological factors.</p> Methods <p>This retrospective, single-center study included patients with surgically staged endometrial cancer. Tumors were classified into p53-abnormal, mismatch repair-deficient (MMRd) and non-specific molecular profile (NSMP) subtypes based on immunohistochemistry. Associations between adnexal involvement and molecular subtypes, preoperative serum CA-125 levels, lymphovascular space invasion (LVSI) and other clinicopathological variables were analyzed.</p> Results <p>Among 661 patients, adnexal involvement was identified in 3.8% (<i>n</i> = 25) and varied significantly across molecular subtypes (<i>p</i> &lt; 0.001). In multivariable analysis, p53-abnormal tumors showed a strong independent association with adnexal involvement (aOR 5.15, 95% CI 1.87–14.19, <i>p</i> = 0.001), whereas NSMP tumors were associated with lower risk. Elevated preoperative CA-125 levels (aOR 1.01, <i>p</i> &lt; 0.001) and the presence of LVSI (aOR 6.62, <i>p</i> &lt; 0.001) were also independent predictors.</p> Conclusion <p>IHC-based molecular subtypes are significantly associated with adnexal involvement in endometrial cancer. Integrating molecular classification with clinicopathological factors may enhance more individualized surgical planning, particularly regarding ovarian preservation decisions.</p>