IMPORTANCE Evidence-based treatments for major depressive disorder (MDD) are not very successful in improving functional and health outcomes. Attention has increasingly been focused on the prevention of MDD. OBJECTIVE To evaluate the effectiveness of a web-based guided self-help intervention for the prevention of MDD. DESIGN, SETTING, AND PARTICIPANTS Two-group randomized clinical trial conducted between March 1, 2013, and March 4, 2015. Participants were recruited in Germany from the general population via a large statutory health insurance company (ie, insurance funded by joint employer-employee contributions). Participants included 406 self-selected adults with subthreshold depression (Centre for Epidemiologic Studies Depression Scale score >= 16, no current MDD according to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition, Text Revision] criteria). INTERVENTIONS All participants had unrestricted access to usual care (visits to the primary care clinician) and were randomized to either a web-based guided self-help intervention (cognitive-behavioral and problem-solving therapy supported by an online trainer; n = 202) or a web-based psychoeducation program (n = 204). MAIN OUTCOMES AND MEASURES The primary outcomewas time to onset of MDD in the intervention group relative to the control group over a 12-month follow-up period as assessed by blinded diagnostic raters using the telephone-administered Structured Clinical Interview for DSM-IV Axis Disorders at 6-and 12-month follow-up, covering the period to the previous assessment. RESULTS Among 406 randomized patients (mean age, 45 years; 73.9% women), 335 (82%) completed the telephone follow-up at 12 months. Fifty-five participants (27%) in the intervention group experienced MDD compared with 84 participants (41%) in the control group. Cox regression analyses controlling for baseline depressive symptom severity revealed a hazard ratio of 0.59 (95% CI, 0.42-0.82; P =.002) at 12-month follow-up. The number needed to treat to avoid 1 new case of MDD was 5.9 (95% CI, 3.9-14.6). CONCLUSIONS AND RELEVANCE Among patients with subthreshold depression, the use of a web-based guided self-help intervention compared with enhanced usual care reduced the incidence of MDD over 12 months. Further research is needed to understand whether the effects are generalizable to both first onset of depression and depression recurrence as well as efficacy without the use of an online trainer.