Background Collaborative care programmes lead to better outcomes in the management of depression. A programme of this nature has demonstrated its effectiveness in primary care in Spain. Our objective was to evaluate the cost-effectiveness of this programme compared to usual care. Methods A bottom-up cost-effectiveness analysis was conducted within a randomized controlled trial (2007-2010). The intervention consisted of a collaborative care programme with clinical, educational and organizational procedures. Outcomes were monitored over a 12 months period. Primary outcomes were incremental cost-effectiveness ratios (ICER): mean differences in costs divided by quality-adjusted life years (QALY) and mean differences in costs divided by depression-free days (DFD). Analyses were performed from a healthcare system perspective (considering healthcare costs) and from a society perspective (including healthcare costs plus loss of productivity costs). Results Three hundred and thirty-eight adult patients with major depression were assessed at baseline. Only patients with complete data were included in the primary analysis (166 in the intervention group and 126 in the control group). From a healthcare perspective, the average incremental cost of the programme compared to usual care was €182.53 (p<0.001). Incremental effectiveness was 0.045 QALY (p=0.017) and 40.09 DFD (p=0.011). ICERs were €4,056/QALY and €4.55/DFD. These estimates and their uncertainty are graphically represented in the cost-effectiveness plane. Limitations The amount of 13.6% of patients with incomplete data may have introduced a bias. Available data about non-healthcare costs were limited, although they may represent most of the total cost of depression. Conclusions The intervention yields better outcomes than usual care with a modest increase in costs, resulting in favourable ICERs. This supports the recommendation for its implementation.