OBJECTIVES: Major depressive disorder (MDD) remains highly under-treated and accounts for substantial health system costs. Duloxetine, a new serotonin and norepinephrine reuptake inhibitor, has been shown to be effective and safe in treatment of depression. This study examined the cost-effectiveness of duloxetine vs. Selective Serotonin Reuptake Inhibitors (SSRIs: fluoxetine, paroxetine, sertraline, citralopram and escitalopram) and venlafaxine extended-release (XR) from the Spanish health system perspective. METHODS: A Markov decision model simulated clinical management of MDD patients during six 2-month cycles in primary or secondary care. Patients on acute treatment could experience remission, response without remission, no response, or discontinuation of initial therapy. Non–responders and partial responders could continue therapy or switch to another therapy. Efficacy data and utility data were derived from clinical trials. Treatment patterns were obtained from interviews with practising Spanish GPs and psychiatrists. Costs from official price/tariff lists were applied. Model outcomes included total treatment cost, quality-adjusted life years (QALYs) and symptom-free days (SFD). The robustness of findings was assessed in sensitivity analyses. RESULTS: In primary care, incremental cost per QALY for duloxetine vs Venalaxine XR was €29,457 and for duloxetine vs SSRIs was between €11,867- €21,957 (extreme values vs paroxetine and fluoxetine, respectively). Incremental cost per SFD was 13€ vs. Venlafaxine XR and ranged from 14€ to 26€ vs. paroxetine and fluoxetine respectively. In secondary care duloxetine was dominant vs. all the drugs except for the comparison with fluoxetine (cost per QALY gained was 650€ and cost per additional SFD was 1€). Results were sensitive to changes in the trial remission and response rates, and in the distribution of switch therapy options. CONCLUSION: Duloxetine showed a reasonable cost-effectiveness ratio vs. the comparator drugs and could therefore be considered a cost-effective treatment for MDD patients in primary and secondary care in Spain.