Objective: Cognitive behaviour therapy (CBT) reduces fatigue and disability in chronic fatigue syndrome (CFS). However, outcomes vary between studies, possibly because of differences in patient characteristics, treatment protocols, diagnostic criteria and outcome measures. The objective was to compare outcomes after CBT in tertiary treatment centres in the Netherlands (NL) and the United Kingdom (UK), using different treatment protocols but identical outcome measures, while controlling for differences in patient characteristics and diagnostic criteria. Methods: Consecutively referred CFS patients who received CBT were included (NL: n = 293, UK: n = 163). Uncontrolled effect sizes for improvement in fatigue (Chalder Fatigue Questionnaire), physical functioning (SF-36 physical functioning subscale) and social functioning (Work and Social Adjustment Scale) were compared. Multiple regression analysis was used to examine whether patient differences explained outcome differences between centres. Results: Effect sizes differed between centres for fatigue (Cohen's D NL = 1.74, 95% CI = 1.52–1.95; UK = 0.99, CI = 0.73–1.25), physical functioning (NL = 0.99, CI = 0.81–1.18; UK = 0.33, CI = 0.08–0.58) and social functioning (NL = 1.47, CI = 1.26–1.69; UK = 0.61, CI = 0.35–0.86). Patients in the UK had worse physical functioning at baseline and there were minor demographic differences. These could not explain differences in centre outcome. Conclusion: Effectiveness of CBT differed between treatment centres. Differences in treatment protocols may explain this and should be investigated to help further improve outcomes.