BACKGROUND: Both depression and smoking have been independently associated with lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. However, no studies have systematically explored the effects of smoking on HRV among depressed patients. PURPOSE: This study examined differences in HRV based on smoking status among depressed individuals. METHODS: Electrophysiological data were examined among 77 adult outpatients without a history of myocardial infarction, who met criteria for major depressive disorder or dysthymia. Frequency domain [low frequency (LF), high frequency (HF), LF/HF ratio, respiratory sinus arrhythmia (RSA)] parameters of HRV, and heart rate and inter-beat interval (IBI) data were compared between depressed smokers (n = 34) and depressed nonsmokers (n = 44). RESULTS: After controlling for covariates, depressed smokers, compared to depressed nonsmokers, displayed significantly lower LF, HF, and RSA. CONCLUSIONS: Among depressed patients, smoking is associated with significantly lower HRV, indicating dysregulated autonomic modulation of the heart.