This study compared the cost-effectiveness of escitalopram to that of citalopram,fluoxetine, and venlafaxine in the treatment of depression in Norway. A two-path decision analytic model with a 6-month horizon was used. Patients start at the primary path and are referred to specialist care in the secondary care path. Model inputs included drug-specific probabilities from comparative trial data, literature, and a panel of experts. The main outcome measure is success (remission), and costs of treatment (total and drug costs). Treatment with escitalopram yielded lower expected cost and greater effectiveness than citalopram, fluoxetine, and venlafaxine. The expected success rate was 64.2% with escitalopram,58.7% with citalopram, 58.7% with fluoxetine, and 62.1% with venlafaxine. Average expected total costs per patient were similar with escitalopram (19,661 Norwegian crowns) and venlafaxine (20,989) and somewhat higher with citalopram (22,379) and fluoxetine (22,558). Budgetary impact estimates a decrease in total health care budget of 72 million crowns. Escitalopram is therefore the most cost-effective alternative and its use would significantly reduce health care costs for the treatment of depression in Norway.