Nineteen identical (monozygotic) and 20 fraternal (dizygotic) sets of twins between 45 and 51 years of age were given nortriptyline orally in doses of 0.2 mg./kg. body weight three times daily for eight days. The steady-state plasma concentrations of nortriptyline were calculated from the mean of the determinations for days 6, 7, and 8. Identical twins, not treated with other drugs, achieved similar steady-state plasma concentrations of nortriptyline in contrast to fraternal twins who were not given other drugs. The intrapair similarity in steady-state plasma concentrations was not found in identical twins simultaneously treated with various drugs during the experiment. Identical and fraternal twins treated with drugs containing barbiturates had considerably lower steady-state plasma concentrations of nortriptyline compared with untreated twins.It is concluded that most of the variability in nor-triptyline steady-state plasma concentration between persons who have not received drugs is genetically determined. Exposure to other drugs also influences the steady-state plasma concentration of nortriptyline, which in a given patient may therefore be determined by a resultant of genetic and environmental factors.