The influence of rifampicin (450 mg/day for 28 days) on the hepatic microsomal enzymes and thyroid function variables were investigated in 13 healthy male volunteers. After 14 and 28 days of treatment a significant increase in median thyroid volume (determined ultrasonically) was demonstrated (20 ml, range 13–28 before; 26 ml, range 18–48 at day 14, and 24 ml, range 17–40 at day 28) (p <0.01). A significant decrease in median serum free T4 index levels was seen (94.1 arbitrary units, range 80.1–123.4 before treatment; 86.8, range 71.7–102.0 at day 14, and 85.3, range 65.5–131.3 at day 28) (p <0.01). Serum T4, T3, T3 resin uptake, free T3 index and TSH levels were not significantly altered. Hepatic microsomal enzyme activity assessed by antipyrine clearance was significantly increased (approximately by 85%) at day 14 and 28, whereafter it normalized. The study supports the hypothesis that the increase in thyroid volume after treatment with rifampicin and other hepatic enzyme system inducers (e.g. phenytoin and carbamazepine) is a compensatory mechanism caused by an increased hepatic degradation of thyroid hormones.