We investigated 98 melanoma patients and 135 normal controls for differences in phenotype and genotype frequencies at the properdin factor B locus. A significant negative association with the Bf-F allele and melanoma was found, resulting in an estimated relative risk of 0.5. The estimated relative risk for developing melanoma among people with the Bf-FF genotype is 0.07. The Bf-S phenotype was significantly increased among the melanoma sample, with an estimated risk of 6.5. The data suggest association of the Bf locus with a melanoma protection and/or susceptibility gene(s).