Catechol-O-methyltransferase (COMT) metabolizes catechol neurotransmitters dopamine, noradrenaline and adrenaline that are involved in various physiological functions including mood, cognition and stress response. Human pain is closely related to all these functions. The gene encoding the COMT enzyme (COMT) has functional polymorphisms that contribute to the interindividual variability in human pain phenotypes such as pain sensitivity, chronicity, severity and response to pain medicine. This review outlines pain symptoms and syndromes that are affected by COMT functional variation, summarizes findings of genetic association studies and provides critical outlook on reported results. Although the exact mechanism of the effect of COMT on human pain is currently uncertain, it has a clear potential to predict clinical outcomes and identify patients at risk for developing pain conditions.