Epidemiological studies have provided evidence that caffeine, an adenosine receptor antagonist, reduces the risk for Parkinson's disease. There are indications of specific interactions between striatal adenosine A(2A) and dopamine D(2) receptors, but the in vivo effects of caffeine on human dopamine system have not been investigated. In the present study, the dopaminergic effects of caffeine were examined with [(11)C]raclopride positron emission tomography (PET) in eight healthy habitual coffee drinkers after 24 h caffeine abstinence. Compared to oral placebo, 200 mg oral caffeine induced a 12% decrease in midline thalamic binding potential (p < 0.001). A trend-level increase in ventral striatal [(11)C]raclopride binding potential was seen with a correlation between caffeine-related arousal and putaminal dopamine D(2) receptor binding (r = -0.81, p = 0.03). The findings indicate that caffeine has effects on dopaminergic neurotransmission in the human brain, which may be differential in the striatum and the thalamus.