Objective Serotonin (5‐HT) is a pleiotropic molecule that exerts several functions on brain and peripheral tissues via different receptors. The gene for the 5‐HT2A receptor shows some variations, including a T102C polymorphism, that have been associated with increased risk of neuropsychiatric and vascular disorders. However, the potential impact of 5‐HT2A imbalance caused by genetic variations on the human lifespan has not yet been established. METHODS We performed a prospective study involving an Amazon riparian elderly free‐living population in Maués City, Brazil, with a 5‐year follow‐up. Out of a cohort of 637 subjects selected in July, 2009, we genotyped 471 individuals, including 209 males (44.4%) and 262 females (55.6%), all averaging 72.3 ± 7.8 years of age (ranging from 60 to 100 years). RESULTS The T102C‐SNP genotypic frequencies were 14.0% TT, 28.0% CC, and 58.0% CT. From 80 elderly individuals who died during the period investigated, we observed significantly (P = .005) higher numbers of TT carriers (27.3%) and CC carriers (21.2%), compared to heterozygous CT carriers (12.5%). Cox‐regression analysis showed that association between the T102C‐SNP and elderly survival was independent of age, sex, and other health variables. CONCLUSIONS Our findings strongly suggest that imbalance in 5‐HT2A may cause significant disturbances that lead to an increased susceptibility to death for individuals who are over 60 years of age.