BACKGROUND: Gamma-glutamyltransferase (GGT), which maintains cellular concentrations of glutathione, may be a marker of oxidative stress, and GGT itself may produce oxidative stress. We performed a prospective study to examine whether serum GGT predicts diabetes and hypertension. METHODS: Study participants were 4844 black and white men and women 18-30 years of age in 1985-1986; they were reexamined 2, 5, 7, 10, and 15 years later. Year 0 GGT cutpoints were 12, 17, 25, and 36 U/L (overall 25th, 50th, 75th, and 90th percentiles; the laboratory cutpoints for abnormal are 40 U/L in women and 50 U/L in men). We deleted 32 participants with prevalent diabetes and 140 participants with prevalent hypertension from the respective incidence analyses. RESULTS: After adjustment for study center, race, sex, and age in proportional hazards regression, the hazard ratios across year 0 GGT categories were 1.0, 1.6, 1.7, 4.0 (95% confidence interval, 2.0-8.1), and 5.5 (2.7-11.1) for 15-year incident diabetes and 1.0, 1.2, 1.7 (1.2-2.2), 2.3 (1.7-3.2), and 2.3 (1.7-3.2) for hypertension. Additional adjustment for year 0 alcohol consumption, body mass index, cigarette smoking, and physical activity attenuated this relationship, but GGT remained a significant predictor. CONCLUSIONS: Serum GGT within a range regarded as physiologically normal is associated with incident diabetes and hypertension. Considering known functionality of GGT, these associations are consistent with a role for oxidative stress in risk for diabetes and hypertension.