The clinical importance of gamma-glutamyltransferase (GGT) has recently been debated. Although some studies have suggested that the relationship between GGT and cardiovascular disease (CVD) mortality is independent of alcohol consumption, to our knowledge no studies have reported the relationship between GGT and CVD mortality in never-drinker subgroups. Since Japanese women are known to have a lower prevalence of alcohol consumption, we examined whether GGT predicts CVD mortality in never-drinkers. We followed 2724 Japanese men and 4122 Japanese women without prior CVD or liver dysfunction for 9.6 years and observed 83 and 82 CVD deaths, respectively. Current alcohol drinkers comprised 59% of men and 7% of women. Among women, the multiple adjusted hazard ratio (HR) for CVD mortality compared with the reference group (GGT: 1-12 U/L) was 2.88 (95% confidence interval (CI), 1.14-7.28) for the elevated group (GGT>or=50 U/L). This positive relationship was unchanged in the never-drinkers subgroup (HR for log-transformed continuous GGT, 1.62 (95% CI, 1.11-2.37)). No significant relationships were observed in men. GGT displays a strong positive association with CVD mortality among Japanese women, for whom the prevalence of ever-drinkers is very low. Exploring the significance and biological mechanisms of GGT might provide useful insights into CVD prevention.