Similarities in the physicochemical properties of caffeine and thiopental would suggest that the apparent volume of distribution of caffeine (aVd) may be comparable to the initial volume of distribution of thiopental. It is the initial volume of distribution of thiopental that is critical in the early minutes of anesthetic induction. A comparison of the aVd of caffeine and thiopental induction dose was made in 21 male New Zealand white rabbits. The aVd of caffeine was determined from serial saliva determinations following intravenous injection of caffeine (7.5 mg/kg). The loss of the pupillary light reflex was used as the end point for induction with thiopental. A statistically significant correlation (r = .722, P less than .0001) was found between the aVd of caffeine and thiopental induction dose. Also, both thiopental induction dose and caffeine aVd decreased significantly with age in these animals. These findings provide a basis for development of an uninvasive test for predicting thiopental dose in humans.