The authors compared the engagement, clinical outcomes, and adverse events of text or voice message-based psychotherapy (MBP) versus videoconferencing-based psychotherapy (VCP) among adults with depression. The study used a sequential multiple-assignment randomized trial design with data drawn from phase 1 of a two-phase small business innovation research study. In total, 215 adults (ages ≥18 years) with depression received care from Talkspace, a digital mental health care company. Participants were initially randomly assigned to receive either asynchronous MBP or weekly VCP. All therapists provided evidence-based treatments such as cognitive-behavioral therapy. After 6 weeks of treatment, participants whose condition did not show a response on the Patient Health Questionnaire-9 or was rated as having not improved on the Clinical Global Impressions scale were randomly reassigned to receive either weekly VCP plus MBP or monthly VCP plus MBP. Longitudinal mixed-effects models with piecewise linear time trends applied to multiple imputed data sets were used to address missingness of data. Participants who were initially assigned to the MBP condition engaged with their therapists over more weeks than did participants in the VCP condition (7.8 weeks for MBP vs. 4.9 weeks for VCP; p<0.001). No meaningful differences were observed between the two groups in rates of change by 6 or 12 weeks for depression, anxiety, disability, or global ratings of improvement. Neither treatment resulted in any adverse events. MBP appears to be a viable alternative to VCP for treating adults with depression.