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To test whether reduction in hostility increases autonomic regulation of the heart.In this randomized controlled trial, participants were 158 healthy adults, aged 20 years to 45 years, who were 1 standard deviation (SD) above national norms on the Cook-Medley Hostility and the Spielberger Trait Anger Indices. Participants also were interviewed, using the Interpersonal Hostility Assessment Technique (IHAT). They were randomly assigned to a 12-week cognitive behavior therapy program for hostility reduction or a wait-list control condition. The main outcome measure was cardiac autonomic modulation, measured as RR interval variability (RRV) derived from 24-electrocardiographic recordings.In a multivariate analysis of variance assessing psychological outcomes of hostility, anger, and IHAT scores, there was a significant treatment effect with an average reduction across the three outcomes that was approximately 0.7 SD (ES = 0.685, SE = 0.184, p < .001) greater for the intervention group than for the control group. In contrast, the change in heart rate was −0.14 beat/min (95% Confidence Interval [CI] = −2.43, 2.14) in treatment participants and −1.36 beat/min (95% CI = −3.28, 0.61) in wait-list participants. High-frequency RRV, an index of cardiac parasympathetic modulation, increased by 0.07 ln ms2 (95% CI = −0.10, 0.24) for participants in the treatment condition and decreased by 0.04 ln ms2 (95% CI = −0.18, 0.10) for participants in the wait-list condition. These differences were not significant. The findings for other indices of RRV were similar.Reduction of hostility and anger was not accompanied by increases in cardiac autonomic modulation. These findings raise questions about the status of disordered autonomic nervous system regulation of the heart as a pathophysiological mechanism underlying the hostility-heart disease relationship and about whether hostility itself is a mechanism or merely a marker of elevated risk of heart disease.