OBJECTIVE: The association between cardiovascular reactivity and major depressive disorder (MDD) remains unclear. This study aimed to examine this association via reactive heart rate variability (HRV) in a well-diagnosed first-episode MDD group and a control group. METHODS: A total of 160 physically healthy, drug-naive patients presenting with their first-episode MDD and 50 healthy controls were recruited. All participants underwent a 5-min electrocardiography at rest and during a mental arithmetic task. Depression severity was assessed using the Beck Depression Inventory II (BDI). RESULTS: HRV measures that showed between-group differences at rest did not reached significance during mental stress. In contrast, HRV measures that revealed between-group differences during stress did not reach significance at rest. In response to mental stress, HRV measures did not significantly change in both group. However, LF and HF in response to stress were different between groups. Patients with MDD revealed an increasing trend in HF and a decreasing trend in LF; conversely, healthy controls had a decreasing trend in HF and an increasing trend in LF. BDI scores correlated with changes in heart rate in the control group. CONCLUSIONS: The fundamental change to reactive HRV in patients with first-episode MDD appears qualitative, not quantitative. A distinctly reverse trend in reactive HRV measures were evident between these two groups. Moreover, patients with MDD showed entirely distinct changes in reactive HRV from those in resting HRV. We suggest that in patients with MDD, autonomic system shifts to sympathetic dominance at rest but toward parasympathetic dominance in response to stress.