GBR12909 (GBR) is a high-affinity, selective, and long-acting inhibitor of dopamine (DA) uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA in the nucleus accumbens of rats. Prior studies showed that intravenous infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR that reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and positron emission tomography (PET). Each baboon underwent paired control/blocked PET scans (performed on three separate study days, 3-4 weeks apart). On the first scan the baboon received saline (3 ml/kg) 90 minutes before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes before the second [11C]WIN 35,428 study. The same experimental design was repeated with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 mg/kg (n = 2), and 10 mg/kg (n = 2) reduced binding potential by 26, 53, and 72%, respectively. GBR was well tolerated in all baboons. These results demonstrate that doses of GBR that suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. These data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that experimental human studies of orally administered GBR to test the DA hypothesis of cocaine addiction should use doses that produce at least 70% occupancy of the DA transporter.