Background: Meta-analyses have been inconclusive about the efficacy of cognitive behaviour therapies (CBTs) delivered in groups of patients with chronic fatigue syndrome (CFS) due to a lack of adequate studies. Methods: We conducted a pragmatic randomised controlled trial with 204 adult CFS patients from our routine clinical practice who were willing to receive group therapy. Patients were equally allocated to therapy groups of 8 patients and 2 therapists, 4 patients and 1 therapist or a waiting list control condition. Primary analysis was based on the intention-to-treat principle and compared the intervention group (n = 136) with the waiting list condition (n = 68). The study was open label. Results: Thirty-four (17%) patients were lost to follow-up during the course of the trial. Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. Large and significant improvement in favour of the intervention group was found on fatigue severity (effect size = 1.1) and overall impairment (effect size = 0.9) at the second assessment. Physical functioning and psychological distress improved moderately (effect size = 0.5). Treatment effects remained significant in sensitivity and per-protocol analyses. Subgroup analysis revealed that the effects of the intervention also remained significant when both group sizes (i.e. 4 and 8 patients) were compared separately with the waiting list condition. Conclusions: CBT can be effectively delivered in groups of CFS patients. Group size does not seem to affect the general efficacy of the intervention which is of importance for settings in which large treatment groups are not feasible due to limited referral.