Background: Depression prevention and early intervention have become a top priority in the Netherlands, but with considerable room for improvement. To address this, Web-based complaint-directed mini-interventions (CDMIs) were developed. These brief and low-threshold interventions focus on psychological stress, sleep problems, and worry, because these complaints are highly prevalent, are demonstrably associated with depression, and have substantial economic impact. Objective: The objective of this economic evaluation was to examine the added value of Web-based, unguided, self-help CDMIs compared with a wait-listed control group with unrestricted access to usual care from both a societal and a health care perspective. Methods: This health economic evaluation was embedded in a randomized controlled trial. The study entailed 2 arms, in which 3 Web-based CDMIs were compared with a no-intervention waiting-list control group (which received the intervention after 3 months). We conducted measurements at baseline, and at 3 and 6 months. The primary outcome was the rate of responders to treatment on depressive symptoms as measured by the Inventory of Depressive Symptomatology Self-Report (IDS-SR). We estimated change in quality of life by calculating effect sizes (Cohen d) for individual pre-and posttreatment IDS-SR scores using a conversion factor to map a change in standardized effect size onto a corresponding change in utility. We calculated incremental cost-effectiveness ratios using bootstraps (5000 times) of seemingly unrelated regression equations and constructed cost-effectiveness acceptability curves for the costs per quality-adjusted life-year (QALY) gained. Results: Of 329 study participants, we randomly assigned 165 to the CDMI group. At 3 months, the rate of responders to treatment was 13.9% (23/165) in the CDMI group and 7.3% (12/164) in the control group. At 3 months, participants in the CDMI group gained 0.15 QALYs compared with baseline, whereas participants in the control group gained 0.03 QALYs. Average ...