Abstract: Objective: Major depressive disorder (MDD) with atypical features is characterized by mood reactivity, increased appetite/weight gain and hypersomnia. Since these characteristics may be associated with obesity and diabetes, we examined whether individuals with MDD with atypical features (MDD-AD) are more likely to exhibit cardiovascular disease than those with MDD without atypical features (MDD-NAD).Methods: Participants in the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of noninstitutionalized US adults, were categorized as having no lifetime depression diagnosis (n=34,979), MDD-NAD (n=4632) and MDD-AD (n=1063) and reported physician-confirmed specific cardiovascular diagnoses in the previous year.Results: Compared to individuals without depression, those with MDD had a 50% increased odds of any cardiovascular diagnosis (P<.0001) independent of sociodemographic factors. Adjusting for sociodemographic differences in MDD subgroups, MDD-AD (compared to MDD-NAD) was associated with 60% (P<.0001) and 43% (P<.005) increases in the odds of hypertension and any cardiovascular diagnosis, respectively. These latter associations were no longer significant after adjusting for body mass index and substance use.Conclusion: Individuals with major depression are at increased risk of heart disease. Whereas major depression with atypical features is associated with certain cardiovascular risk factors, there is no greater risk of cardiovascular diagnoses.