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Abstract Background Catechol-O-methyltransferase (COMT Val158Met) has been implicated in both depression and cardiovascular disease. The purpose of this study was to assess if COMT Val158Met, which influences the COMT enzyme activity, has an effect on the risk of cardiovascular disease (CVD) in individuals with a history of depression and also to determine if the risk differs depending on gender. Methods Data from a longitudinal cohort study of mental health among Swedish adults was used. Depression was assessed twice 3 years apart for each participant, in 1998–2001 and 2001–2003. Saliva DNA was contributed by 4349 (41.7%) of the participants and 3525 was successfully genotyped for COMT Val158Met. Participants were followed up until December 2014 from the National Patient register with regard to cardiovascular outcomes (hypertensive or ischemic heart disease, and stroke). Results Those with depression and the high COMT enzyme activity genotype (Val/Val) had almost a three-fold increased risk of later CVD (OR 3.6; 95% CI: 2.0-6.6) compared to those non-depressed carrying the Val/Val allele. This effect on risk for CVD was higher in women compared to men (OR 7.0; 95% CI: 3.0-14.0 versus OR 2.1; 95% CI: 1.0-6.8). Both additive interaction (attributable proportion (AP) = 0.56; 95% CI: 0.24-0.90 and synergy index (SI) = 4.39; 1.0-18.7) and multiplicative interaction (log likelihood test p = 0.1) was present between depression and COMT Val158Met in predicting risk of later CVD. Conclusion High COMT activity genotype Val158Met increased the risk of CVD in depressed persons. The risk was higher in women compared to men.