Breast cancer radiotherapy can be an emotionally difficult experience. Despite this, few studies have examined the effectiveness of psychological interventions to reduce negative affect, and none to date have explicitly examined interventions to improve positive affect among breast cancer radiotherapy patients. The present study examined the effectiveness of a multimodal psychotherapeutic approach, combining cognitive-behavioral therapy and hypnosis (CBTH), to reduce negative affect and increase positive affect in 40 women undergoing breast cancer radiotherapy. Participants were randomly assigned to receive either CBTH or standard care. Participants completed weekly self-report measures of positive and negative affect. Repeated and univariate analyses of variance revealed that the CBTH approach reduced levels of negative affect [F(1, 38)=13.49; p=.0007, ω2=.56], and increased levels of positive affect [F(1, 38)=9.67; p=.0035, ω2=.48], during the course of radiotherapy. Additionally, relative to the control group, the CBTH group demonstrated significantly more intense positive affect [F(1, 38)=7.09; p=.0113, d=.71] and significantly less intense negative affect [F(1, 38)=10.30; p=.0027, d=.90] during radiotherapy. The CBTH group also had a significantly higher frequency of days where positive affect was greater than negative affect (85% of days assessed for the CBTH group versus 43% of the Control group) [F(1, 38)=18.16; p=.0001, d=1.16]. Therefore, the CBTH intervention has the potential to improve the affective experience of women undergoing breast cancer radiotherapy. © 2009 Wiley Periodicals, Inc. J Clin Psychol 65: 1–13, 2009.