Context: High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system. Objectives: To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depressionrelated measurement bias. Design: A placebo-controlled trial. Setting: Research clinics. Patients: Adult patients with moderate to severe MDD randomized to receive paroxetine (n=120), placebo (n=60), or cognitive therapy (n=60). Outcome Measures: NEO Five-Factor Inventory and Hamilton Rating Scale for Depression. Results: Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P<.001; extraversion, P=.002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P=.46) or extraversion (P=.14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, -1.2 SD, P<.001), they reported little change on neuroticism (-0.18 SD, P=.08) or extraversion (0.08 SD, P=.50). Cognitive therapy produced greater personality change than placebo (P≥.01); but its advantage on neuroticism was no longer significant after controlling for depression (P=.14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P=.003) but not among cognitive therapy responders (P=.86). Conclusions: Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state effect hypothesis and instead support the notion that SSRIs' effects on personality go beyond and perhaps contribute to their antidepressant effects. ©2009 American Medical Association. All rights reserved.