Background: Cancer related fatigue is prevalent and disabling. When persistent and unexplained, it is termed post-cancer fatigue (PCF). Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) may improve symptoms and functional outcomes. Methods: A randomised control trial - Treatment of Post-cancer fatigue Study (TOPS) assigned patients to an education intervention, or a 12 week integrated CBT and GET intervention supervised by an exercise physiologist and clinical psychologist. Three months post treatment for breast or colon cancer, eligible patients had: clinically-significant fatigue; no co-morbid medical or psychiatric conditions which explained the fatigue; and no clinical or laboratory evidence of cancer recurrence. The education arm included a single visit with clinicians describing the principles of CBT/GET and an education booklet. The CBT/GET arm included fortnightly individually tailored consultations. The primary outcome measures were self-reported fatigue (SOMA subscale - SPHERE questionnaire; (0 – 12)) and functional status (Role limitation due to physical health problems – SF36 questionnaire (0 – 100)) comparing baseline, end treatment (12 weeks), and follow-up (24 weeks). Outcomes were analysed by ‘clinically-significant’ improvement designated a priori as ≥ one standard deviation improvement in fatigue scores. Results: 160 patients were screened, and 34% (n = 55) were eligible. The primary reason for ineligibility was sub-threshold fatigue (n = 61, 58%). 46 patients were enrolled, including 43 women (94%), with a mean age of 51 years. Intention-to-treat analysis showed that fatigue severity improved in all enrolled subjects improved from a mean of 5.2 ± 3.1 to 3.9 ± 2.8 at week 12, suggesting a natural history of improvement. Clinically significant improvement was observed in 7 of 22 subjects in the intervention group compared to 2 of 24 in the education group (p < 0.05, χ2). These subjects had a mean improvement in functional status (SF-36) of 25.4 ± 33.3 compared to non-responders (6.0 ± 15.3, p < 0.01, t test). Conclusions: Combined CBT/GET improves fatigue and functional outcomes for a subset of patients with PCF. Further studies to improve the response rate are warranted.