Several studies suggest that human longevity appears to be linked inextricably with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in loci that regulate the immune response, as human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genes. It has been suggested that longevity is associated with positive selection of alleles (i.e., HLA-DR11) or haplotypes (i.e., HLA-B8,DR3) that confer resistance to infectious disease(s). On the other hand, the cytolytic activity of natural killer (NK) cells is controlled by activating and inhibitory cell-surface receptors, including KIR. The genetic diversity of the KIR loci with respect to successful aging has been analyzed only in one study performed in the Irish population. Although two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. We have evaluated by polymerase chain reaction-sequence-specific primers (PCR-SSP) HLA-DRB1 and KIR receptors/HLA ligands frequencies in centenarians and controls from Sicily. Our results demonstrate an increase of the HLA DRB1*18 allele in male centenarians (p = 0.0266, after Bonferroni correction). Concerning KIR, no significant difference was observed after Bonferroni correction. However, our findings suggest that HLA/KIR/longevity associations are population specific, being heavily affected by the population-specific genetic and environmental history. This kind of study is important to better understand aging and longevity, hence enhancing the planning of antiaging strategies.