The X chromosome inactivation pattern in peripheral blood cells becomes more skewed after age 55, and a genetic effect on this age-related skewing has been reported. We investigated the effect of age on X inactivation phenotype in blood, buccal cells and tissue from duodenal biopsies in 80 females aged 19–90 years. The X inactivation pattern correlated positively with age in blood (r= 0.238, P= 0.034) and buccal cells (r= 0.260, P= 0.02). The mean degree of skewing was higher in the elderly (≧ 55 years) than in the young (< 55 years) in blood (70.1 and 63.5%, respectively, P= 0.013) and in buccal cells (64.7 and 59.0%, respectively, P= 0.004). Correlation of X inactivation between the different tissues was high in all tissues with a tendency to increase with age for blood and buccal cells (P= 0.082). None of the duodenal biopsies had a skewed X inactivation, and the mean degree of skewing was similar in the two age groups. The tendency for the same X chromosome to be the preferentially active X in both blood and buccal cells with advancing age is in agreement with a genetic effect on age-related skewing and indicates that genes other than those involved in hematopoiesis should be investigated in the search for genes contributing to age related skewing.