Treatment of chronic myeloid leukaemia (CML) with IFN-alpha (IFN) is known to confer significant survival benefit, but the drug's impact on quality of life (QoL) in CML is unclear. We describe a cross-sectional comparison of QoL in patients randomised to long-term treatment with IFN versus no IFN within the UK MRC CML 3 trial, assessing the long-term consequences and psychosocial side effects of IFN therapy. Patients completed the EORTC QoL QLQ-C30, an in-house leukaemia/IFN questionnaire, a brief assessment of sexual functioning and demographic details. In total, 163 eligible patients completed questionnaires (85% response). Patients receiving IFN reported significantly worse QoL for emotional, cognitive and social functioning, pain and dyspnoea (P<0.01), and marginally worse fatigue, nausea and vomiting (P<0.05). As expected from other IFN use, those on IFN experienced more flu-like and febrile symptoms and skin problems than those not on IFN. In all, 35% of patients stopped IFN before questionnaire completion. This made no material difference to the results, except that those continuing on IFN had slightly better self-assessed Global health/QoL than those who had stopped (P<0.03). IFN treatment adversely affected sexual health after allowing for age and gender. In conclusion, IFN treatment has a significant adverse impact on QoL. Patient awareness of the survival benefits and these QoL effects should enable better-informed decision-making. The impact on QoL of IFN dose, and of imatinib therapy versus IFN in early CP CML, are being investigated. QoL will need evaluating in future studies of combination treatment (IFN+imatinib).