Cystic fibrosis (CF) is the most common lethal genetic disease in Europeans and is transmitted as an autosomal recessive disorder caused by loss of function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Since long it has been supposed that its quite high frequency (1/2500 implying an allele frequency equal to 0.02) is due to a Europe-restricted selective advantage of the heterozygous CF/þ individuals. Nevertheless, this hypothesis has never been directly demonstrated nor the hypothetical selective factor identified. Here, we provide compelling evidence that the CF/þ advantage hypothesis is right. As to the identification of the selective factor, as the CFTR protein is a ClÀ channel (and hence involved in water excretion), diarrhea appears a reasonable candidate for such a role. Cholera has, in fact, been suggested, but its area of diffusion had not been limited to Europe. Considering that initially all humans were lactose intolerant in the post-weaning life and Europeans became cattle breeders and adopted a dairy-milk diet, we propose that the hypothetical Europe-restricted CF/þ advantage consisted of a resistance to lactose-caused diarrhea in populations that adopted such a habit while they were still lactose intolerant. This initial emergency segregational load adaptation would have been followed by a not costly one consisting of the present European quasi-fixed post-weaning lactase persistence (due to the dominant P allele of the lactase, LCT, gene), resulting in lactose tolerance. This hypothesis is supported by the positive correlation between the proportion, among the CF alleles, of the F508del allele and the P allele–recently identified with the T allele 14 Kb upstream to the LCT gene–frequency and provides a possible explanation for the well-known north–south cline of the F508del allele frequency.