The association of serum levels of gamma-glutamyltransferase (GGT) with cardiovascular disease risk factors, and with mortality from all causes, cardiovascular disease, and non-cardiovascular diseases, has been examined in a prospective study of 7,613 middle-aged British men followed for 11.5 years. GGT levels were strongly associated with all-cause mortality, largely due to a significant increase in deaths from ischemic heart disease and other non-cardiovascular disease causes, i.e., non-cancer deaths, in the top quintile of the GGT distribution. No association was seen with cancer mortality. However, GGT was significantly (positively) associated with alcohol intake, body mass index, smoking, preexisting ischemic heart disease, diabetes mellitus, antihypertensive medication, systolic and diastolic blood pressure, total and high density lipoprotein cholesterol, heart rate, and blood glucose, and negatively associated with physical activity and lung function (forced expiratory volume in 1 second (FEV1)). After adjustment for these personal characteristics and biologic variables, elevated GGT (highest quintile > or = 24 unit/liter vs. the rest) was still associated with a significant increase in mortality from all causes (relative risk (RR) = 1.22, 95% confidence interval (CI) 1.01-1.42; n = 818 deaths) and from ischemic heart disease (RR = 1.42, 95% CI 1.12-1.80; n = 332 deaths). The increase in other non-cardiovascular disease causes was of marginal significance (RR = 1.45, 95% CI 0.95-2.20; n = 127 deaths). When examined separately by the presence or absence of preexisting ischemic heart disease, the increased risk of ischemic heart disease mortality was more marked in those with evidence of ischemic heart disease at screening, particularly in those with previous myocardial infarction (RR = 1.67, 95% CI 1.03-2.69; n = 84 deaths). The increased risk of other non-cardiovascular disease deaths was only seen in men without preexisting ischemic heart disease, largely due to an excess of hepatic cirrhosis. In summary, many factors other than alcohol intake are associated with increased levels of GGT, in particular body mass index, diabetes mellitus, and serum total cholesterol. The finding of increased risk of ischemic heart disease mortality seen in men with preexisting ischemic heart disease is related to the severity of the underlying myocardial damage. The biologic significance of raised GGT in men with preexisting ischemic heart disease merits further study.