OBJECTIVES: To determine the cost-effectiveness of interventions for major depression in Thailand.  METHODS: A microsimulation model was developed to describe the course of disease in individuals. Model inputs included Thai data on disease parameters and costs while impact measures are derived from a systematic review and meta-analysis of the international literature. Results are presented as cost (Thai Baht) per disability adjusted life year (DALY) averted, compared to the null scenario (do nothing). Fluoxetine as the cheapest antidepressant drug in Thailand was analysed for treatment of episodes plus a 6 month continuation phase and for maintenance treatment over five years of follow-up. Cognitive behavioral therapy (CBT) was analysed for episodic treatment and for 5-year maintenance treatment. RESULTS: The incremental cost-effectiveness ratios (ICER) of fluoxetine for episodic treatment with or without a continuation or maintenance phase are just below 1 times GDP per capita in Thailand of 110,000 Baht. CBT during an episode of depression (ICER=39,000) is more cost-effective than medications (ICER=88,000); a maintenance version of CBT is the most cost-effective option with an ICER of 27,000.  Episodic drug treatment has the lowest cost (250 Million Baht) and averts 3000 DALYs. Episodic treatment with CBT, which has an ongoing effect for 1.5 years, costs 100 Million Baht more than drug treatment but it averts more than 6000 DALYs compared to drugs. CONCLUSIONS: CBT is the most cost-effective treatment option for both episodic and maintenance treatment. Maintenance treatment is the more cost-effective of the two. However, there is currently a lack of mental health personal, especially psychiatrists and psychologists, who would be expected to deliver CBT in Thailand. Antidepressant drugs are quite a bit less effective but also less costly than CBT.