ObjectivesTo assess whether a history of major depressive disorder (MDD) in middle-aged individuals with hypertension influences first-onset cardiovascular disease outcomes.DesignProspective cohort survival analysis using Cox proportional hazards regression with a median follow-up of 63 months (702 902 person-years). Four mutually exclusive groups were compared: hypertension only (n=56 035), MDD only (n=15 098), comorbid hypertension plus MDD (n=12 929) and an unaffected (no hypertension, no MDD) comparison group (n=50 798).SettingUK Biobank.ParticipantsUK Biobank participants without cardiovascular disease aged 39–70 who completed psychiatric questions relating International Classification of Diseases-10 Revision (ICD-10) diagnostic criteria on a touchscreen questionnaire at baseline interview in 2006–2010 (n=134 860).Primary and secondary outcome measuresFirst-onset adverse cardiovascular outcomes leading to hospital admission or death (ICD-10 codes I20–I259, I60–69 and G45–G46), adjusted in a stepwise manner for sociodemographic, health and lifestyle features. Secondary analyses were performed looking specifically at stroke outcomes (ICD-10 codes I60–69 and G45–G46) and in gender-separated models.ResultsRelative to controls, adjusted HRs for adverse cardiovascular outcomes were increased for the hypertension only group (HR 1.36, 95% CI 1.22 to 1.52) and were higher still for the comorbid hypertension plus MDD group (HR 1.66, 95% CI 1.45 to 1.9). HRs for the comorbid hypertension plus MDD group were significantly raised compared with hypertension alone (HR 1.22, 95% CI 1.1 to 1.35). Interaction measured using relative excess risk due to interaction (RERI) and likelihood ratios (LRs) were identified at baseline (RERI 0.563, 95% CI 0.189 to 0.938; LR p=0.0116) but not maintained during the follow-up.LimitationsPossible selection bias in UK Biobank and inability to assess for levels of medication adherence.ConclusionsComorbid hypertension and MDD conferred greater hazard than hypertension alone for adverse cardiovascular outcomes, although evidence of interaction between hypertension and MDD was inconsistent over time. Future cardiovascular risk prediction tools may benefit from the inclusion of questions about prior history of depressive disorders.