OBJECTIVES: This analysis estimated the cost-utility of second-line treatment for major depressive disorder using generic selective serotonin reuptake inhibitors (SSRIs), escitalopram, paroxetine CR, sertraline or venlafaxine XR. METHODS: A Markov probabilistic decision analysis was constructed with cycle dependent transition probabilities for persistency over 52 weeks, examining whether persistent patients would have a response, and if this response was followed by remission. Response was °Ý50% improvement from baseline in depression rating score. Remission was defined as °Ü7 HAM-D or °Ü10 MADRS. Remission and response rates were obtained from published clinical trials and entered into the model using beta distributions. Utilities were based on duration of treatment and changed weekly over the year. Baseline utility scores were 0.35, 0.21, and 0.30 for remission, response, and treatment failure, respectively; between days 56-365 utility scores were 0.85, 0.72, and 0.58, respectively. Wholesale acquisition costs were used for medication costs. Remission, response, and treatment failure costs were obtained from the literature and were estimated using gamma distributions. The analysis was conducted using 10,000 Monte Carlo simulations with first- and second-order sampling procedures. RESULTS: The lowest cost option was generic SSRI agents ($3283), with the highest being venlafaxine XR ($4111). The effectiveness was greatest for venlafaxine XR (35.2 quality-adjusted life weeks (QALWs), followed by escitalopram (34.1), sertraline (34.1), generic SSRIs (33.8), and paroxetine CR (33.4). Cost per QALW ranged from $97 for generic SSRIs to $117 for venlafaxine XR. The incremental cost effectiveness ratio (ICER) for venlafaxine XR relative to generic SSRIs was $609. When QALW are converted to quality-adjusted life years (QALYs), the ICER per QALY for venlafaxine XR relative to generic SSRIs was $31,621. CONCLUSIONS: Using a Monte Carlo Markov model, the analysis suggests that venlafaxine XR is more effective in terms of QALWs and has an acceptable ICER relative to generic SSRIs.