Since early after the introduction of serum gamma-glutamyltransferase (GGT) in clinical practice as a reliable and widely employed laboratory test, epidemiological and prospective studies have repeatedly shown that this activity possesses a prognostic value for morbidity and mortality. The association is independent of possibly concomitant conditions of liver disease, and notably, a significant independent correlation of serum GGT exists with the occurrence of cardiovascular diseases (myocardial infarction, stroke). Experimental work has documented that active GGT is present in atherosclerotic plaques of coronary as well as in cerebral arteries. These findings, and the recently recognized functions of GGT in the generation of reactive oxygen species, indicate that serum GGT represents a true marker of cardiovascular diseases and underlying atherosclerosis. Further insights into potential therapeutic interest will probably be derived from studies investigating the origin of GGT activity in plaque tissue.