Fatigue affects a majority of patients undergoing cancer-related therapies. We conducted a study of 954 adult cancer patients presenting for treatment at our hospital between April 2001 and November 2004 to quantify the relationship between fatigue and patient satisfaction with quality of life (QoL). Fatigue was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire fatigue subscale. Patient satisfaction with QoL was measured using the Ferrans and Powers Quality of Life Index (QLI). The relationship between fatigue and QLI was evaluated using univariate and multivariate linear regression after controlling for the effects of clinical and demographic factors. Of the 954 patients, 579 were females and 375 males, with a median age at presentation of 56 years (range 20-90 years). Sixty-six percent had failed prior treatment. The most common cancers were breast (26%), colorectal (19%), and lung (16%) cancers. After controlling for the effects of age and prior treatment history, every 10-unit increase in fatigue was statistically significantly associated with 1.5-, 0.22-, 0.77-, 0.27-, and 0.85-unit declines in QLI health and physical, social and economic, psychological and spiritual, family, and global function scores, respectively. Consequently, a 30-point increase in fatigue score correlates with a 4.5-point decline in QLI health functioning-a clinically significant decline. In our study, we found that fatigue is strongly associated with patient satisfaction with QoL independent of the effects of age and prior treatment history.