Alpha-actinin-3 (ACTN3) is a sarcomeric protein localised to the Z-line of type II muscle fibres. A nonsense polymorphism in the ACTN3 gene (p.R577X) has been identified; the X/X genotype is present in ~16% Caucasians and results in ACTN3 deficiency. R577X genotype has been associated with altered muscle performance and function in elite athletes and among the general population. Reduced muscle function is an established risk factor for falling in the elderly, which is a significant public health problem. We therefore tested the hypothesis that ACTN3 genotype variation is associated with the incidence of falling in elderly women. We studied 1313 Caucasian postmenopausal women aged 60-80 years from the North of Scotland Osteoporosis Study for whom DNA samples were available (mean age 69.7 ± 5.5 years). Self-reported data on falls was collected at recruitment and at 4- and 6-year follow-ups. ACTN3 genotyping was performed by DdeI restriction digest. Case-control association analyses were performed using PLINK statistical genetics software. Cross-sectional analysis of fallers versus non-fallers at baseline was performed. Further, individuals who reported having fallen at more than one time point (recurrent fallers) were compared with those who did not report falling at any time point (never fell). Correction for potential confounders (age, height, weight) was performed by logistic regression. Power was calculated using the Quanto program. Genotype frequencies for baseline fallers (n=349) and non-fallers (n=871) were R/R=28%, R/X=53%, X/X=19% and R/R=30%, R/X=51%, X/X=19%, respectively. For recurrent fallers (n=113) versus never fell (n=271), frequencies were R/R=27%, R/X=56%, X/X=17% and R/R=29%, R/X=49%, X/X=22%, respectively. There was no significant association between ACTN3 genotype and falls (baseline or recurrent) under any model, even with correction. These findings indicate that ACTN3 R577X does not play a major role in influencing falls risk in elderly women. The sample size examined here has >80% power to detect additive effects with odds ratio of 1.3 for each copy of allele X. However, muscle function is one of many complex interacting risk factors for falls, and individual genetic effects on falls risk – as for other common, complex disorders – will likely be smaller. We are in the process of genotyping a further 3300 samples from another cohort of elderly women to enable us to examine this further.