Background: A substantial minority of adolescents suffer from depression and it is associated with increased risk of suicide, social and educational impairment, and mental health problems in adulthood. A recently conducted randomized controlled trial in England evaluated the effectiveness of a manualized universally delivered age-appropriate CBT programme in school classrooms. The cost-effectiveness of the programme for preventing low mood and depression for all participants from a health and social care sector perspective needs to be determined. Methods: A trial-based cost-effectiveness analysis based on a cluster-randomized controlled trial (trial registration--ISRCTN 19083628) comparing classroom-based CBT with usual school provision of Personal Social and Health Education. Per-student cost of intervention was estimated from programme records. The study was undertaken in eight mixed-sex UK secondary schools, and included 3,357 school children aged 12 to 16 years (in the two trial arms evaluated in the cost-effectiveness analysis). The main outcome measures were individual self-reported data on care costs, Quality-Adjusted Life-Years (QALYs, based on the EQ-5D health-related quality-of-life instrument) and symptoms of depression (Short Mood and Feelings Questionnaire) at baseline, 6 and 12 months. Results: Although there was lower quality-adjusted life-years over 12 months (-0.05 QALYs per person, 95% confidence interval -0.09 to -0.005, p = 0.03) with CBT, this is a "clinically" negligible difference, which was not found in the complete case analyses. There was little evidence of any between-arm differences in SMFQ scores (0.19, 95% CI -0.57 to 0.95, p = 0.62), or costs (£142, 95% CI -£132 to £415, p = 0.31) per person for CBT versus usual school provision. Conclusions: Our analysis suggests that the universal provision of classroom-based CBT is unlikely to be either more effective or less costly than usual school provision.