BACKGROUND: The estimated prevalence of comorbid major depressive disorder (. MDD) is 11% in patients with type 2 diabetes (T2D) and 15-20% in those with cardiovascular disease (CVD). Comorbid MDD continues to be a significant source of economic burden to the healthcare system. METHODS: We assessed the incremental healthcare burden of comorbid MDD in patients with T2D or CVD. This real-world, retrospective, administrative claims study analyzed commercially insured adults with T2D or CVD diagnosed on at least 2 separate claims within 12 months of each other (between January 1, 2011, and September 30, 2018). CVD included congestive heart failure, peripheral vascular disease, coronary heart disease, and cerebrovascular disease. The study compared patients with and without MDD with either T2D or CVD. Study assessments included all-cause healthcare resource utilization (proportion of patients with hospitalization, emergency department [ED] visits, and outpatient visits) and cost. RESULTS: Patients were matched by propensity score for demographics and baseline characteristics, resulting in similar baseline characteristics for the respective subcohorts. After matching, 22,892 patients with T2D (11,446 each with and without MDD) and 28,298 patients with CVD (14,149 each with and without MDD) were included. At follow-up, patients with T2D and MDD had significantly higher rates of hospitalization (26.1% vs 17.4%, P < 0.0001) and ED visits (55.3% vs 43.0%, P < 0.0001) than those observed in patients without MDD. The total cost for patients with T2D and MDD at follow-up was significantly higher than for those without MDD ($16,511 vs $11,550, P < 0.0001). Similarly, at follow-up, patients with CVD and MDD had significantly higher rates of hospitalization (45.4% vs 34.1%, P < 0.0001) and ED visits (66.5% vs 55.4%, P < 0.0001) than those observed in patients without MDD. Total cost at follow-up for patients with CVD and MDD was significantly higher than for those without MDD ($25,546 vs $18,041, P < 0.0001). CONCLUSIONS: Patients with either T2D or CVD and comorbid MDD have higher total all-cause healthcare utilization and cost than similar patients without MDD. Study findings reinforce the need for appropriate management of MDD in patients with these comorbid diseases, which in turn may result in cost reductions for payers. TRIAL REGISTRATION: Not applicable.