Objective: The study purpose was to test the effectiveness of a psychological intervention combining cognitive-behavioral therapy and hypnosis (CBTH) to treat radiotherapy-related fatigue. Design: Women (n = 42) scheduled for breast cancer radiotherapy were randomly assigned to receive standard medical care (SMC) (n = 20) or a CBTH intervention (n = 22) in addition to SMC. Participants assigned to receive CBTH met individually with a clinical psychologist. CBTH participants received training in hypnosis and CBT. Participants assigned to the SMC control condition did not meet with a study psychologist. Main Outcome Measures: Fatigue was measured on a weekly basis by using the fatigue subscale of the Functional Assessment of Chronic Illness Therapy (FACIT) and daily using visual analogue scales. Results: Multilevel modeling indicated that for weekly FACIT fatigue data, there was a significant effect of the CBTH intervention on the rate of change in fatigue (p < .05), such that on average, CBTH participants' fatigue did not increase over the course of treatment, whereas control group participants' fatigue increased linearly. Daily data corroborated the analyses of weekly data. Conclusion: The results suggest that CBTH is an effective means for controlling and potentially preventing fatigue in breast cancer radiotherapy patients.