BACKGROUND: Depressive disorders are known to be associated with higher risks of cardiovascular diseases. Several studies have reported an imbalance within the autonomic nervous system (ANS) as one putative cause. Previous investigations showed decreased cardio-respiratory coupling in depressive patients that were treated with nortriptyline. We aimed to compare parameters of heart rate variability and cardio-respiratory coupling between unmedicated patients suffering from major depressive disorder (MDD) and healthy controls in order to further understand autonomic dysfunction in the disease. METHODS: We investigated eighteen unmedicated patients with major depressive disorder and eighteen matched healthy controls. Electrocardiogram and respiratory signals were obtained during a twenty minute resting period. Time- and frequency based parameters of HRV, respiratory sinus arrhythmia (RSA), approximate entropy of heart rate (ApEn(RR)) and respiratory rate (ApEn(Resp)) were calculated. Additionally, cross-ApEn between RR-intervals and respiration time series was determined, reflecting coupling of both signals. RESULTS: Patients showed an increased heart rate and LF/HF-ratio. Respiratory sinus arrhythmia (RSA) and ApEn(RR) were reduced in patients in comparison to controls. Breathing rate, ApEn(Resp) and cross-ApEn did not differ between the two groups. DISCUSSION: Increased heart rate, increased LF/HF-ratio, reduced RSA and reduced ApEn(RR) indicate a decrease of cardiac vagal modulation in depressive patients. No difference of cardio-respiratory coupling was observed. Respiratory parameters and cross-ApEn did not differ between both groups, and thus we conclude that diminished vagal modulation is mainly limited to cardiac modulation.