Context Cancer-related fatigue is prevalent and disabling. When persistent and unexplained, it is termed post-cancer fatigue (PCF). Cognitive behavioral therapy (CBT) and graded exercise therapy (GET) may improve symptoms and functional outcomes. Objectives To evaluate the outcomes of a randomized controlled trial, which assigned patients with post-cancer fatigue to education, or 12 weeks of integrated cognitive-behavioral therapy (CBT) and graded exercise therapy (GET). Methods Three months after treatment for breast or colon cancer, eligible patients had clinically significant fatigue, no comorbid medical or psychiatric conditions that explained the fatigue, and no evidence of recurrence. The CBT/GET arm included individually tailored consultations at approximately two weekly intervals. The education arm included a single visit with clinicians describing the principles of CBT/GET and a booklet. The primary outcome was clinically significant improvement in self-reported fatigue (Somatic and Psychological HEalth REport 0–12), designated a priori as greater than one SD of improvement in fatigue score. The secondary outcome was associated improvement in function (role limitation due to physical health problems—36-Item Short Form Health Survey 0–100) comparing baseline, end treatment (12 weeks), and follow-up (24 weeks). Results There were 46 patients enrolled, including 43 women (94%), with a mean age of 51 years. Fatigue severity improved in all subjects from a mean of 5.2 (±3.1) at baseline to 3.9 (±2.8) at 12 weeks, suggesting a natural history of improvement. Clinically significant improvement was observed in 7 of 22 subjects in the intervention group compared with 2 of 24 in the education group (P < 0.05, χ2). These subjects also had improvement in functional status compared with nonresponders (P < 0.01, t-test). Conclusion Combined CBT/GET improves fatigue and functional outcomes for a subset of patients with post-cancer fatigue. Further studies to improve the response rate and the magnitude of the benefit are warranted.