The present study investigated for a possible effect on fertility of four longevity candidate genes (ACE, PON1, PPAR-gamma, APOE) in order to determine whether they have a pleiotropic action at different life ages. The study population was 151 healthy unrelated subjects. Only PPAR-gamma and APOE showed an effect on fertility. The PPAR-gamma Pro/Ala genotype, which had showed an association with longevity only in men, was found associated only in men with having produced more children (6.1+/-3.3) than the Pro/Pro genotype (3.3+/-1.9; P=0.001). APOE*2 allele, which has been consistently associated with longevity, was confirmed to be associated with the lowest fertility (P=0.03). The logistic regression analysis indicated that APOE and PPAR-gamma polymorphisms may be considered independent determinants of reproductive efficiency. These data suggest that the APOE*2 allele follows the model of antagonist pleiotropy, while the PPAR-gamma Pro/Ala genotype seems to exert beneficial effects both early in life and in advanced age in a gender-specific way.