The effects of caffeine (250 mg orally) on plasma free fatty acids (FFA), urinary catecholamines, and drug binding were studied in 16 normal subjects (six men, five women on oral contraceptives, and five women not on oral contraceptives). FFA doubled 1 hr after caffeine, and remained elevated for at least 4 hr. with elevation of each FFA. Urinary excretion of epinephrine and dopamine increased (p<0.05) in the first 2 hr. returning to baseline in the next 2 hr. Plasma binding of chlordiazepoxide, diaxepam, and propranolol was estimated in each of the hourly plasma samples after caffeine; there was no change in percent unbound drug in any of the samples. In vitro addition of oleic acid to plasma samples of four subjects caused a step-wise increase in percent unbound fraction of all three drugs whereas in vitro addition of caffeine did not further alter drug binding. In our study circulating plasma FFA and urinary catecholamine levels were elevated after caffeine ingestion. In spite of a rise in FFA, there was, however, no change in plasma binding of chlordiazepoxide, diazepam, or propranolol.