Nurse-led self-help treatments for people with chronic fatigue syndrome/myalgic encephalitis (CFS/ME) have been shown to be effective in reducing fatigue but their cost-effectiveness is unknown. OBJECTIVES: To determine the cost-effectiveness of alternative treatment options for people with CFS/ME in a primary care setting. Design and setting Cost-effectiveness analysis conducted alongside a single blind randomised controlled trial comparing pragmatic rehabilitation (PR) and supportive listening (SL) delivered by primary care nurses, and treatment as usual (TAU) delivered by the general practitioner (GP) in North West England. METHODS: A total of 296 patients aged 18 and over with CFS/ME diagnosed using the Oxford criteria. A within trial analysis was conducted comparing the costs and quality adjusted life years (QALYs) measured within the time frame of the trial.  RESULTS: Treatment as usual is less expensive and leads to better patient outcomes compared with Supportive Listening. Treatment as usual is also less expensive than Pragmatic Rehabilitation.  PR was effective at reducing fatigue in the short term, but the impact of the intervention on QALYs was uncertain.  However, based on the results of this trial, PR is unlikely to be cost-effective in this patient population. CONCLUSIONS: This analysis does not support the introduction of SL.  Any benefits generated by PR are unlikely to be of sufficient magnitude to warrant recommending PR for this patient group on cost-effectiveness grounds alone.  However, dissatisfaction with current treatment options means simply continuing with ‘treatment as usual’ in primary care is unlikely to be acceptable to patients and practitioners.