Two hundred and ninety-five patients with persistent back pain and subclinical depression were randomized to receive standard treatment for back pain plus a web-based self-help intervention for depression (eSano BackCare-DP) or standard back pain treatment alone for the prevention of major depressive episodes (MDEs). The primary outcome of interest was the onset of a MDE within the 12 month follow-up period. Secondary outcomes of interest included clinician-rated depression severity (Hamilton Depression Rating Scale (HAM-D), Quick Inventory Depressive Symptomology (QIDS), and self-rated depression severity (PHQ-9). Additional outcomes included pain on a numeric rating scale (NRS), quality of life (Assessment of Quality of life [AQoL-6D]), pain related disability (Oswestry Disability Index [ODI]), pain self-efficacy (Pain Self-Efficacy Questionnaire [PSEQ]), work capacity (Subjective Prognostic Employment Scale [SPE]), and user satisfaction (Client Satisfaction with Online Interventions Questionnaire 8). Outcomes were assessed up to 12 months post-treatment. Results demonstrated that a statistically significantly lower incidence of depression onset was observed in the intervention group compared to the control group (p<0.001) at 12 months follow-up. Depression severity as measured by HAM-D, QIDS, PHQ-9 were all significantly in favour of the intervention group up to 12 months post-treatment. Moreover, ODI scores, PSEQ scores, and AQoL-6D scores were significantly in favour of the intervention group up to 12 months post-treatment. No significant differences in NRS pain scores and SPE scores, or the incidence of adverse events were observed between the two groups up to 12 months post-treatment.