Objective: Determine whether a novel psychosocial treatment for positive affect improves clinical status and reward sensitivity more than a form of cognitive behavioral therapy that targets negative affect and whether improvements in reward sensitivity correlate with improvements in clinical status. Method: In this assessor-blinded, parallel-group, multisite, two-arm randomized controlled clinical superiority trial, 85 treatment-seeking adults with severely low positive affect, moderate-to-severe depression or anxiety, and functional impairment received 15 weekly individual therapy sessions of positive affect treatment (PAT) or negative affect treatment (NAT). Clinical status measures were self-reported positive affect, interviewer-rated anhedonia, and self-reported depression and anxiety. Target measures were eleven physiological, behavioral, cognitive, and self-report measures of reward anticipation-motivation, response to reward attainment, and reward learning. All analyses were intent-to-treat. Results: Compared to NAT, individuals receiving PAT achieved superior improvements in the multivariate clinical status measures at posttreatment, b = .37, 95% CI .15, .59, t(109) = 3.34, p = .001, q = .004, d = .64. Compared to NAT, individuals receiving PAT also achieved higher multivariate reward anticipation-motivation, b = .21, 95% CI .05, .37, t(268) = 2.61, p = .010, q = .020, d = .32, and higher multivariate response to reward attainment, b = .24, 95% CI .02, .45, t(266) = 2.17, p = .031, q = .041, d = .25, at posttreatment. Measures of reward learning did not differ between the two groups. Improvements in reward anticipation-motivation and in response to reward attainment correlated with improvements in the clinical status measures. Conclusions: Targeting positive affect results in superior improvements in clinical status and reward sensitivity than targeting negative affect. This is the first demonstration of differential target engagement across two psychological interventions for anxious or depressed individuals with low positive affect. What is the public health significance of this article? This study demonstrates that positive affect treatment was significantly more effective than an intervention that targeted negative affect for adults with severely low positive affect, moderate-to-severe depression or anxiety, and functional impairment. The findings of this study suggest that positive affect treatment improves positive affect and aspects of reward hyposensitivity.