High dehyroepiandrosterone (DHEA) or dehydroepiandrosterone sulphate (DHEAS) levels have been suggested to be protective for cardiovascular disease. DHEA supplementation is reported to lower low-density levels of cholesterol in humans and to reduce atherosclerotic plaques in rabbits. Several prospective studies have examined the relationship between DHEAS levels and cardiovascular disease but results have been conflicting. In men, estimated relative risks associated with one standard deviation increase in DHEAS levels range between 0.63 for coronary heart disease mortality in the Rancho Bernardo Study, 0.45 for fatal coronary heart disease but 1.11 for non-fatal coronary heart disease in the Honolulu Heart Study, 0.90 for myocardial infarction in the US Male Physicians study, and 1.34 in the Helsinki Heart Study. The only prospective study reporting data in women, the Rancho Bernardo Study, found DHEAS levels were not significantly associated with cardiovascular mortality. Variability in findings between studies may reflect the different endpoints used (DHEAS may influence mortality but not incidence), or may indicate a more complex relationship between DHEAS and other biological processes directly causally related to cardiovascular disease, which may vary in different age and sex groups. Cigarette smoking may be an important confounder since it increases cardiovascular disease risk but is also associated with increased DHEAS levels. It is notable that populations which have the lowest coronary heart disease rates and greatest longevity such as the Japanese also reportedly have low mean DHEAS levels, so DHEAS per se does not appear to explain between-population differences in cardiovascular incidence or longevity. Intervention studies in humans to examine the effect of pharmacological or physiological doses of DHEA on biological variables such as lipid levels, glucose tolerance and insulin sensitivity have been limited in size and duration and results have been inconsistent. While the data to date are intriguing, the clinical significance of DHEA and DHEAS in cardiovascular disease remains uncertain. There is still a lack of understanding of the basic biological effects of DHEA and DHEAS and further data both in men and in women from prospective studies and randomized trials are urgently needed.