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Background: Web-based cognitive-behavioral interventions to reduce substance use can be a useful low-cost treatment for a large number of people, and an attractive option in countries where a greater availability of treatment is needed. Objective: To evaluate the feasibility and initial effectiveness of a web-based cognitive-behavioral intervention for the reduction of substance use and depression compared with treatment as usual, with and without a printed self-help manual. Method: Individuals seeking outpatient treatment for substance use were randomly assigned to one of the following: (1) the web-based Help Program for Drug Abuse and Depression (n = 23); (2) an in-person session with an addiction therapist and use of the Alcohol, Smoking, and Substance Involvement Screening Test Self-Help Strategies guide, followed by treatment as usual (n = 25), or (3) treatment ordinarily offered in the participating treatment centers (n = 26). The study took place in 2013-2014 (trial registration: ISRCTN25429892), and participants completed baseline, posttreatment, and 1-month follow-up evaluation interviews. Results: Treatment retention and data availability were comparable in all three conditions. A reduction was observed from baseline to follow-up in average days of use [F(1,28) = 29.70, p < 0.001], severity of use [F(2,28) = 143.66, p < 0.001], and depressive symptomatology [F = (4)16.40, p < 0.001], independent of the type of treatment provided. Conclusions: The findings suggest that the web-based intervention to reduce substance abuse is feasible, although it is not more effective than other intervention modalities; its effectiveness must be evaluated in a larger sample. Attrition was a main limitation; future studies must improve retention and assess cost-effectiveness. [ABSTRACT FROM AUTHOR]