There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT(2A) binding in the brain and responses to noxious heat stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT(2A) antagonist, [(18)F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [(18)F]altanserin binding in orbitofrontal (r=0.66; p=0.005), medial inferior frontal (r=0.60; p=0.014), primary sensory-motor (r=0.61; p=0.012) and posterior cingulate (r=0.63; p=0.009) cortices. In contrast, measures of regional [(18)F]altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT(2A) receptor availability co-varies with responses to tonic pain. The correlation between [(18)F]altanserin binding in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation and/or cognitive-evaluative appreciation of pain.