e21560 Background: Adjuvant immunotherapy can improve outcomes for resected stage IIB/C melanoma patients, but also poses challenges. Many patients are cured by surgery alone, making them susceptible to unnecessary treatment risks. Additionally, current staging may overlook some high-risk stage IIA patients who could benefit from immunotherapy. Accurate risk assessment is therefore critical to balance benefits and risks of early immunotherapy and optimise patient selection. This study sought to identify clinicopathologic predictors to refine risk stratification for sentinel lymph node-negative (SLN(-)) stage II melanoma patients, with a focus on the role of sex in prognostic accuracy and treatment personalisation. Methods: We retrospectively analysed 565 stage II melanoma patients with negative sentinel lymph node biopsies at four UK hospitals between 2004-2017. The primary outcome was progression-free survival (PFS). Analysed clinicopathologic factors included Breslow thickness, ulceration sex and tumour-infiltrating lymphocytes (TILs). Univariate and multivariate analyses were conducted. Results: Median follow-up was 9.5 years. Melanoma progression occurred in 24% of patients. Sex emerged as a significant PFS predictor. Specifically, stage IIA and IIB males had higher progression risks than females at the same stages. We also observed disparities across stages; for instance, PFS was significantly worse in stage IIA males than stage IIB females (PFS difference: χ2 = 5.629, p = 0.018), revealing gaps in the prognostic accuracy of current staging systems. Stage IIB females—identified as at risk by current standards—had 5-year PFS of 91%. This highlights potential overestimation of their treatment needs and subsequent risk of undue exposure to treatment toxicity. The sex-based discrepancies observed may be partially explained by differences in antitumor immune function, evidenced by the discovery that Non-brisk TILs-an independent predictor of high progression risk in SLN(-) stage II melanoma- were associated with a 20% reduction in PFS in males vs females (p < 0.001). Conclusions: Significant sex-based PFS disparities exist among sentinel lymph node-negative stage II melanoma patients, with implications for treatment decisions. Incorporating sex enables more refined risk assessment than current substaging alone. Specifically, stage IIA males may be under-recognised for progression risks, while many stage IIB females could face overtreatment. Our findings advocate for nuanced, sex-specific approaches to enhance prognostic accuracy and optimise patient care.