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Purpose: To evaluate the prognostic role of soluble CD163 (sCD163) in serum and macrophage infiltration in primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. The scavenger receptor CD163 is associated with anti-inflammatory macrophages, and it is shed from their surface., Patients and Methods: Serum samples from 227 patients with stage I/II melanoma obtained before definitive surgery (baseline) and during 5 years of follow-up were analyzed for sCD163 by enzyme-linked immunosorbent assay. Excised formalin-fixed, paraffin-embedded primary melanomas from 190 patients were available for immunohistochemical analyzes of CD163(+) and CD68(+) macrophage infiltration. They were estimated semiquantitatively in three different tumor compartments: tumor nests, tumor stroma, and at the invasive front of the tumor., Results: Serum sCD163 treated as an updated continuous covariate as well as the baseline value were analyzed together with the covariate's ulceration and thickness in a Cox proportional hazards model. sCD163 was an independent prognostic factor for overall survival (baseline, hazard ratio [HR] = 1.4; 95% CI, 1.1 to 1.7; P = .01; and updated, HR = 1.4; 95% CI, 1.1 to 1.8; P = .003). Melanomas with dense CD163(+) macrophage infiltration in tumor stroma and CD68(+) macrophage infiltration at the invasive front were associated with poor overall survival (CD163, HR = 2.7; 95% CI, 0.8 to 9.3; P = .11; and CD68, HR = 2.8; 95% CI, 1.2 to 6.8; P = .02) independent (borderline for CD163) of thickness and ulceration., Conclusion: Both serum levels of sCD163 and the presence of CD68(+) macrophage infiltration at the tumor invasive front are independent predictors of survival in AJCC stage I/II melanoma. CD163(+) cell infiltration in tumor stroma may be predictive of survival.