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We have previously reported on the familial aggregation of bipolar II affective disorder and have speculated that new treatment approaches might be required for this difficult disorder. Based on Reimherr's report that fluoxetine responders were more likely to have poor prior responses to tricyclics and to have chronic depressions with “atypical” clinical features, we used fluoxetine to treat the chronic atypical depression in selected bipolar II outpatients. The 16 bipolar II patients in our series had been depressed for an average of 5.3 years prior to starting fluoxetine and had had poor responses to tricyclics, MAOIs, and lithium. All but one have had some response to fluoxetine. Ten of the 13 patients who have been taking fluoxetine for 10 or more months have had a good to very good response and the other 3 have had a fair response. Only one patient discontinued fluoxetine because of side effects. These findings should encourage further treatment research using fluoxetine and other serotonin reuptake blockers as well as research into the pathophysiologic identity of bipolar II as a possible distinct form of affective disorder.