To better define the incidence and range of elevated gamma-glutamyl transpeptidase (GGT) activity in patients taking a drug known to induce hepatic microsomal enzymes, GGT was measured in the sera of 58 patients before and after six months of phenytoin therapy. Enzyme activity at six months was greater than baseline in 52 of 58 patients (90%). GGT activity (normal, 0-50 units/liter) was 45.2 +/- 9.9 (mean +/- SEM) at baseline and 135.8 +/- 18.1 after six months of therapy, a mean threefold increase (P less than 0.001). Of the 45 patients with normal baseline GGT activity, some had marked elevation of serum GGT activity with values rising over 200 units/liter in eight patients and over 300 units/liter in four patients. Mean serum GGT activity remained significantly elevated at 12 and 24 months. This elevation in GGT activity was not influenced by age, sex, or additional anticonvulsant drug therapy. Both baseline and six-month GGT activity was lowest in patients who drank no alcohol, higher in patients who drank 0-1 pint/week, and greatest in patients who drank greater than 1 pint/week. All 13 patients with elevated baseline GGT activity were regular users of alcohol and/or taking other enzyme-inducing drugs. In conclusion, increase in serum GGT activity occurs in 90% of patients on long-term phenytoin therapy, most often to moderate but occasionally to high levels, and this rise in GGT activity is accentuated by regular consumption of alcohol.