BCG vaccine, vaccinia vaccine and certain pathogens that were shown in previous studies to protect against melanoma have antigenic determinants homologous in their amino acids sequence with the melanoma antigen HERV-K-MEL, encoded by a human endogenous retrovirus K (HERV-K), which is expressed in about 95% of malignant melanocytes. Yellow fever vaccine (YFV) likewise contains an antigenic determinant with a close homology to HERV-K-MEL and might therefore also confer protection against melanoma. To investigate this possibility we carried out a cohort study (28,306 subjects) and a nested case-control study (37 melamona cases and 151 tumors not expressing HERV-K-MEL) in Veneto region (North-Eastern Italy). The standardized incidence ratio was 1.33 (95% confidence interval, 0.84-2.11), 1.59 (0.97-2.59) and 0.59 (0.19-1.84), while the age- gender-adjusted odds ratios were 1.00, 0.96 (0.43-2.14) and 0.26 (0.07-0.96), at 0-4, 5-9, and > or =10 years elapsed from YFV administration, respectively. The risk of melanoma may therefore be lowered 10 years after vaccination with yellow fever vaccine.