Health-related quality of life (HRQoL) is a key issue for patients with chronic lymphocytic leukemia. The multicenter LRF CLL4 trial, in which 777 patients were randomized to receive chlorambucil or fludarabine, alone or with cyclophosphamide (FC), assessed HRQoL at baseline, months 3, 6 and 12, then annually until 5 years, using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30). While on treatment, some HRQoL impairment was seen in patients receiving fludarabine, particularly FC, compared with chlorambucil. Thus at 3 months, role/social functioning and fatigue were ≥ 10 points worse than baseline in 41%/46%/56%, respectively, of patients receiving fludarabine alone and 48%/54%/60% receiving FC, compared with only 29%/31%/40% of those receiving chlorambucil. Thereafter HRQoL appeared similar between treatment groups. Sustained remissions were associated with long-term HRQoL benefit. In the primary HRQoL domains patients still in complete or partial remission at each time-point had scores close to those reported in general population studies, while patients whose disease had progressed had mean scores up to 22 points worse, in spite of subsequent treatments. These data offer support for the use of primary treatment regimens likely to achieve and sustain remission in otherwise medically fit patients of all ages, including those aged > 70 years.