We found that ICOS CpG 4/5 methylation, ICOS mRNA, and pathologic stage were independent prognostic biomarkers in melanoma (ICOS mRNA HR = 0.995 [95%CI 0.992–0.999], P = 0.009; ICOS CpG 4/5 methylation: HR = 0.248 [95%CI 0.098–0.623], P = 0.003; pathologic stage: HR = 1.424 [95%CI 1.122–1.808], P = 0.004). The gene discussed is ICOS; the disease is melanoma.