Catechol-O-methyltransferase (COMT) is the major enzyme involved in the catabolism of dopamine, a neurotransmitter in the brain’s reward system. The common COMT polymorphism Val158Met (rs4680 G>A) modulates pain response to opioids through a reward-motivated mechanism; however, its role in nonpharmacological pain medicine has not been clinically characterized. We genotyped 325 participants from a randomized controlled trial of cancer survivors with chronic musculoskeletal pain. We found that carrying methionine at position 158 (158Met) of COMT, encoded by the A allele, significantly increased the analgesic response to electroacupuncture (74% versus 50%; odds ratio [OR]: 2.79; 95% confidence interval [CI]: 1.31, 6.05; p<0.01), but not to auricular acupuncture (68% versus 60%; OR: 1.43; 95% CI: 0.65, 3.12; p=0.37) or usual care (24% versus 18%; OR: 1.46; 95% CI: 0.38, 7.24; p=0.61) compared to Val/Val. These findings raise the possibility that COMT Val158Met might be an important predictor of analgesic response to electroacupuncture, providing novel insights into precision non-pharmacologic pain management tailored to individual genetic backgrounds. PERSPECTIVE: This work suggests the modulating effects of the polymorphism in COMT Val158Met on the response to acupuncture. Further research needs to validate these findings, increase the mechanistic understanding of acupuncture, and guide further development of acupuncture as a precision pain management strategy.