The association of TP53 P72R (rs1042522) with longevity remains uncertain and varies with ethnicity. Here, we tested its association with longevity in a cross-sectional population of Central Italy (18-106 years, N = 1,072), by integrating demographic information and frequency data to account for the different survival rates between sexes through the application of a genetic-demographic approach. rs1042522 affects females longevity, showing significant associations in Comparison 2 (Age Class 3 [>91 years] vs Age Class 2 [73-91 years]) under both additive (odds ratio [OR] 0.574; p = .006) and dominant (OR 0.513; p = .006) models. The TP53*P72 allele is significantly underrepresented in Age Class 3 only in women (OR 0.575; p = .008). The genetic-demographic approach demonstrated that the frequency of female TP53*P72 carriers underwent a significant reduction after 82 years (OR 0.586; p = .002). The same analyses gave nonsignificant results in men. The discrepancies among the results obtained on rs1042522 for longevity could result from the pleiotropic effects of p53 and the potential ethnic variation of its functional variants.