The plasma protein binding of caffeine in young and elderly males was evaluated using an ultrafiltration technique. In spite of a significantly lower plasma albumin concentration in the elderly subjects the observed percent bound (approximately 35%) was essentially identical in both subject groups. The binding of caffeine to human plasma albumin (4.5% w/v) in vitro was also examined using ultracentrifugation and it was observed to be bound to the extent of 37.8%. In both the plasma and albumin binding studies the free fraction remained constant over the range of concentrations examined. Although there was no apparent correlation between the percent bound and the albumin concentration in the plasma of either subject group the close agreement between the degree of binding of caffeine to albumin and human plasma indicates that albumin is likely the major plasma binding protein for caffeine.