Although a diagnosis of chronic lymphocytic leukemia (CLL) can have a profound effect on the quality of life (QOL), few studies have objectively measured the QOL of CLL patients or compared it to the general population. We conducted an international, web-based survey of patients with CLL using standardized instruments with published population norms to evaluate fatigue and QOL. Co-morbid health conditions were assessed using the Charlson Co-Morbidity Index. Between June and October 2006, 1482 patients with CLL responded to the survey. The physical, social/family, functional, and overall QOL scores of CLL patients were similar to or better than published population norms. In contrast, the emotional well-being scores of CLL patients were dramatically lower than that of both the general population (P < 0.001) and patients with other types of cancer (P < 0.001). QOL scores were lower among individuals with advanced stage disease (all P < 0.05). Factors associated with lower overall QOL on multivariate analysis included older age, greater fatigue, severity of co-morbid health conditions, and current treatment. CLL has a profound impact on QOL at all disease stages. The effects of CLL on QOL appear to differ from that of other malignancies with a more marked impact on emotional QOL. Research identifying efficacious psycho-oncologic support interventions for patients with CLL is needed.