The authors conducted exploratory analyses to determine whether specific symptoms of major depressive disorder (MDD) are associated with cardiac disease in 4,041 outpatients at baseline in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. MDD was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; depressive symptoms were evaluated with the 30-item Inventory of Depressive Symptomatology, Clinician-Rated; and cardiac disease, with the Cumulative Illness Rating Scale. After adjustments for gender, age, ethnicity, education, and employment status, sympathetic arousal and early-morning insomnia were significantly associated with cardiac disease. Prospective studies are warranted to confirm these results.