We investigated clozapine (CLZ) tissue pharmacokinetics in vivo by using carbon-11-labeled CLZ ((11)C-CLZ) and positron emission tomography (PET). Eight healthy volunteers underwent (11)C-CLZ studies wherein computed tomography image acquisition was followed by PET scans (whole-body, four; brain, four). After bolus intravenous (11)C-CLZ injection, PET images were acquired at various timepoints for 2-3 hours. Tissue (11)C-CLZ signals were plotted over time, and pharmacokinetic parameters were determined. High (11)C-CLZ radioactivity was detected in the liver and brain, implying CLZ hepatic metabolism and efficient blood-brain barrier penetration. The urinary and hepatobiliary tracts were involved in (11)C-CLZ excretion. Moderate to high radioactivity was observed in the dopaminergic and serotonergic receptor-rich brain regions, indicating CLZ binding to multiple receptor types. To our knowledge, this is the first study to report the determination of (11)C-CLZ tissue pharmacokinetics in humans. PET using radiolabeled drugs can provide valuable information that could complement plasma pharmacokinetic data.