<p dir="ltr">Background. Although depression is a risk factor for cardiovascular disease (CVD), few clinical trials in people without CVD have examined the effect of depression treatment on CVD-related outcomes. It’s unknown if successful depression treatment improves indicators of CVD risk, such as CVD-relevant health behaviors, traditional CVD risk factors, and CVD events. </p><p dir="ltr">Methods. We examined data from eIMPACT trial, a phase II randomized controlled trial conducted from 2015-2020. Depressive symptoms, CVD-relevant health behaviors (self-reported CVD prevention medication adherence, sedentary behavior, and sleep quality) and traditional CVD risk factors (blood pressure and lipid fractions) were assessed. Incident CVD events over four years were identified using a statewide health information exchange. </p><p dir="ltr">Results. The intervention group exhibited greater improvement in depressive symptoms (p < 0.01) and sleep quality (p < 0.01) than the usual care group, but there was no intervention effect on systolic blood pressure (p = 0.36), low-density lipoprotein cholesterol (p = 0.38), high-density lipoprotein cholesterol (p = 0.79), triglycerides (p = 0.76), CVD prevention medication adherence (p = 0.64), or sedentary behavior (p = 0.57). There was an intervention effect on diastolic blood pressure that favored the usual care group (p = 0.02). CVD-relevant health behaviors did not mediate any intervention effects on traditional CVD risk factors. Twenty-two participants (10%) experienced an incident CVD event. The likelihood of an CVD event did not differ between the intervention group (12.1%) and the usual care group (8.3%; HR = 1.45, 95% CI: 0.62-3.40, p = 0.39). </p><p dir="ltr">Conclusions. Successful depression treatment alone improves self-reported sleep quality but is not sufficient to lower CVD risk of people with depression. Alternative approaches may be needed reduce CVD risk in depression. </p><p dir="ltr">Trial Registration: ClinicalTrials.gov Identifier: NCT02458690 </p><p dir="ltr">Keywords: depression, cardiovascular disease, blood pressure, lipids, medication adherence, sedentary behavior, sleep quality, collaborative care, internet interventions, clinical trial</p>