Objective: The relationship between fatigue and pain has been investigated previously, but little is known about the prevalence of substantial fatigue in patients sick-listed for chronic low back pain (CLBP) and about how fatigue is associated with depression, pain, and long-term disability. The aims of the study were to examine the prevalence of substantial fatigue; associations between fatigue, depression, and pain; and whether fatigue predicted long-term disability. Methods: Five hundred sixty-nine patients participating in a randomized controlled trial and sick-listed 2–10 months for LBP were included in the study. Cross-sectional analyses were conducted to investigate the prevalence and independent associations between fatigue, depression, pain, and disability, while longitudinal analyses were done to investigate the association between fatigue and long-term disability. Results: The prevalence of substantial fatigue was 69.7%. Women reported significantly more fatigue than men (t = −3.6, df = 551; P < .001). Those with substantial fatigue had higher pain intensity (t = −3.3, df = 534; P = 0.01), more depressive symptoms (t = −10.9, df = 454; P < 0.001), and more disability (t = −7.6, df = 539; P < 0.001) than those without substantial fatigue. Musculoskeletal pain and depression were independently associated with substantial fatigue. In the longitudinal analyses, fatigue predicted long-term disability at 3, 6, and 12 months' follow-up. After pain and depression were controlled for, fatigue remained a significant predictor of disability at 6 months' follow-up. Conclusions: The vast majority of the sick-listed CLBP patients reported substantial fatigue. Those with substantial fatigue had more pain and depressive symptoms and a significant risk of reporting more disability at 3, 6, and 12 months. Substantial fatigue is disabling in itself but also involves a risk of developing chronic fatigue syndrome and long-term disability