The authors investigated the association of the catechol-o-methyltransferase (COMT) gene Val158Met polymorphism with delirium risk and functional and cognitive outcomes among patients with complicated mild to moderate traumatic brain injury (TBI). In a prospective observational cohort study, patients were monitored for occurrence of delirium during the first 4 days of admission by using the Confusion Assessment Method. Functional and cognitive outcomes were evaluated with the Glasgow Outcome on Discharge Scale and the Montreal Cognitive Assessment test, respectively. Eighty-nine patients were included in the study; of these, 17 (19%) were diagnosed with delirium. The COMT Val158/Val158 polymorphism was associated with increased risk of delirium in multivariable regression analyses adjusted for alcohol misuse, history of neurological disorder, age, and admission Glasgow Coma Scale score (odds ratio=4.57, 95% CI=1.11, 18.9, p=0.036). The COMT Met158 allele was associated with better functional outcomes in univariate analysis (odds ratio=2.82, 95% CI=1.10, 7.27, p=0.031) but not in multivariable analysis (odds ratio=2.33, 95% CI=0.89, 6.12, p=0.085). Cognitive outcomes were not associated with the COMT Val158Met polymorphism in univariate regression analysis (p=0.390). Delirium was a significant predictor of worse functional and cognitive outcomes in multivariable regression analyses adjusted for other risk factors (odds ratio=0.04, 95% CI=0.01, 0.16, p<0.001, and β=-3.889, 95% CI=-7.55, -0.23, p=0.038, respectively). The COMT genotype is important in delirium risk and functional outcomes of patients with mild to moderate TBI. Whether the COMT genotype is associated with outcomes through incident delirium remains to be determined in larger studies.