BACKGROUND:early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability. OBJECTIVE:to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality. DESIGN:population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals. PARTICIPANTS:genetic data are available for 1,805 individuals. METHODS:each of six genotypes of three common alleles of the APOE locus (epsilon 2, epsilon 3 and epsilon 4) was tested on the association with a disability index or mortality. RESULTS:APOE epsilon 3/epsilon 3 genotype significantly decreases odds ratio (OR) for IADL disability in males [OR = 0.48; 95% Confidence Interval (CI) 0.31-0.76] while it exhibits no association in females. The OR for ADL disability is 0.19 (CI 0.04-0.99) for epsilon 4/epsilon 4 female carriers. The epsilon 2/epsilon 3 genotype increases the chances of IADL disability for males (OR = 2.33; CI 1.28-4.25). No significant association between APOE polymorphism and mortality was found. A surprising observation was that epsilon 4/epsilon 4 female carriers have a 5.3 times lower chance of having ADL disability than non-epsilon 4/epsilon 4-carriers. CONCLUSIONS:association of the APOE polymorphism with disability and lack of association with mortality support the view that APOE gene actions may be more significant as modulators of frailty than of longevity.