Background: Major depression is an important and costly problem among adolescents, yet evidence to support the provision of cost-effective treatments is lacking. Aims: To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression. Method: Pragmatic randomised controlled trial in the UK. Outcomes and costs were assessed at baseline, 12 and 28 weeks. Results: The trial comprised 208 adolescents, aged 11-17 years, with major or probable major depression who had not responded to a brief initial psychosocial intervention. There were no significant differences in outcome between the groups with and without CBT. Costs were higher in the group with CBT, although not significantly so (P=0.057). Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 3056 probability that CBT plus SSRIs is more cost-effective than SSRIs alone. Conclusions: A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care.