[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT(2A)) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT(2A) receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT(2A) receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT(2A) receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT(2A) receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT(2A) receptors in the human brain.