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 total costs per patient at 3 months were €2094 for the CDMI group and €2230 for the control group (excluding baseline costs). Bootstrapped seemingly unrelated regression equations models resulted in a dominant incremental cost-effectiveness ratio (ie, lower costs and a higher rate of responders to treatment) for the CDMI group compared with the control group at 3 months, with the same result for the costs per QALY gained. Various sensitivity analyses attested to the robustness of the findings of the main analysis. Conclusions: Brief and low-threshold Web-based, unguided, self-help CDMIs have the potential to be a cost-effective addition to usual care for adults with mild to moderate depressive symptoms. The CDMIs improved health status, while reducing participant health care costs, and hence dominated the care-as-usual control condition. As intervention costs were relatively low, and the internet is readily available in the Western world, we believe CDMIs can be easily implemented on a large scale.