The effects of caffeine on plasma adenosine were examined in eight healthy normal volunteers. Subjects were randomly administered on 4 separate days, in a double-blind fashion, either placebo or three different doses of caffeine (240, 480, and 720 mg). Adenosine concentrations, measured by high performance liquid chromatography, were in the micromolar range when samples were drawn into tubes containing dipyridamole to prevent adenosine reuptake by red blood cells. Plasma adenosine levels did not change after caffeine administration. The effects of caffeine on anxiety were related to changes in plasma caffeine but not plasma adenosine levels. The potential interest of caffeine as a chemical model of anxiety is discussed.