High levels of dysfunctional attitudes have been associated with greater severity of depression and poorer response to pharmacological treatment. The goal of our study was to examine this relationship and the changes in dysfunctional attitudes after treatment with fluoxetine, a relatively selective serotonin uptake inhibitor. Dysfunctional attitudes were evaluated with both the Cognitions Questionnaire (CQ) and the Dysfunctional Attitudes Scale (DAS) in 115 outpatients diagnosed as having major depressive disorder. After 8 weeks of treatment with fluoxetine, 67 of these patients again completed the DAS and the CQ. Dysfunctional attitudes were associated with depression severity both before and after treatment and decreased linearly with treatment of the depression. Negative thinking and dysfunctional attitudes, as measured by both DAS and CQ, were not predictive of the degree of improvement in depressive symptoms. These findings partly support a state-dependent interpretation of dysfunctional attitudes, and provide evidence of significant reductions in these attitudes after treatment with a serotonin uptake inhibitor.