The interleukin-10 gene (IL-10) is polymorphic. The genotypes result in inter-individual differences in IL-10 production, which may play a role in the pathophysiology and the clinical course of melanoma and other cancers. We analyzed the frequency of the ATA haplotype formed by the alleles at -1082 (G/A), -819 (C/T), and -592 (C/A) at the promoter region of the IL-10 gene in patients with melanoma (n = 108) and healthy subjects (n = 393). We also studied the long-term prognostic significance of the ATA haplotype carriage. There were significantly more ATA carriers in melanoma patients compared with control subjects (44 vs. 33%, respectively, P = 0.03). In the patients who presented with localized disease, the haplotype carriage was not significantly associated with recurrence rate, disease-free survival, or overall survival. In the patients who presented with or developed advanced disease (n = 36), the ATA haplotype carriage [HR 0.47, 95% confidence interval (CI) 0.22-1.01, P = 0.05] was found statistically significant when adjusted by metastatic sites (HR 4.63, 95% CI 1.88-11.44, P = 0.0009) in multivariate analysis for survival. ATA haplotype carriage appears to increase the susceptibility to melanoma. This is not a significant prognostic factor in localized melanoma, but in advanced disease, it implies longer survival.