It is widely accepted that there is marked inter-individual variation in platelet function, although this has not been formally studied in large numbers of subjects. We have recruited and studied three large populations: one to characterize platelet variation and the factors responsible for it; a second to estimate heritabilities of the variation in platelet function; and a third to test for interactions between platelet genes and hormone therapy in postmenopausal women. We find that platelet variability is substantial, inherited and can be reproducibly detected. We genotyped 2145 women in the Heart and Estrogen/progestin Replacement Study followed for coronary heart disease (CHD) events for 6 years and found that common combinations of polymorphisms in the genes for GPIbalpha and GPVI were associated with hormone therapy harm, benefit or no effect. If corroborated in future studies, platelet genotyping could be used to predict postmenopausal hormone safety.