The newer antidepressants have fewer side effects than older antidepressants, and are more expensive.We review cost-effectiveness literature comparing newer with older antidepressants, comprising one prospective, four retrospective, and 15 simulation studies. Methodologic issues limit the conclusions that can be drawn from most of these studies. Additional research is needed before it will be possible to consider the question of whether newer antidepressants are cost effective from a societal perspective. From a healthcare system perspective, the limited evidence available tends to suggest that routine first-line treatment with newer antidepressants at current prices may not be cost-effective for the initial and maintenance treatment durations recommended by current practice guidelines. More prospective research is needed before substantial confidence may be placed in this conclusion.