Hostility is associated with an increased risk for cardiovascular disease (CVD). Because central serotonin may modulate aggression, we might expect selective serotonin reuptake inhibitors (SSRIs) to be effective in reducing hostility. Such effects have never been examined in individuals scoring high on hostility who are otherwise free from major Axis I psychopathology according to criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., Text Revision; American Psychiatric Association, 2000). A total of 159 participants (ages 30?50 years, 50% female) scoring high on 2 measures of hostility and with no current major Axis I diagnosis were randomly assigned to 2 months of citalopram (40 mg, fixed-flexible dose) or placebo. Adherence was assessed by electronic measurement and by drug exposure assessment. Treated participants showed larger reductions in state anger (Condition x Time; p = .01), hostile affect (p = 02), and, among women only, physical and verbal aggression (p = .005) relative to placebo controls. Treatment was also associated with relative increases in perceived social support (p = .04). The findings have implications for understanding the central nervous system correlates of hostility, its associations with other psychosocial risk factors for CVD, and, potentially, the design of effective interventions.