Decreased heart rate variability (HRV) is a cardiovascular predictor of mortality. Recent debate has focused on whether reductions in HRV in major depressive disorder (MDD) are a consequence of the disorder or a consequence of pharmacotherapy. Here we report on the impact of transcranial direct current stimulation (tDCS), a non-pharmacological intervention, vs. sertraline to further investigate this issue. The employed design was a double-blind, randomized, factorial, placebo-controlled trial. One hundred and eighteen moderate-to-severe, medication-free, low-cardiovascular risk depressed patients were recruited for this study and allocated to either active/sham tDCS (10 consecutive sessions plus two extra sessions every other week) or placebo/sertraline (50 mg/d) for 6 wk. Patients were age and gender-matched to healthy controls from a concurrent cohort study [the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)]. The impact of disorder, treatment and clinical response on HRV (root mean square of successive differences and high frequency) was examined. Our findings confirmed that patients displayed decreased HRV relative to controls. Furthermore, HRV scores did not change following treatment with either a non-pharmacological (tDCS) or pharmacological (sertraline) intervention, nor did HRV increase with clinical response to treatment. Based on these findings, we discuss whether reduced HRV is a trait-marker for MDD, which may predispose patients to a host of conditions and disease even after response to treatment. Our findings have important implications for our understanding of depression pathophysiology and the relationship between MDD, cardiovascular disorders and mortality.