Few studies have evaluated sex differences in the prevalence, severity, and correlates of fatigue at the end of life. The Brief Fatigue Inventory, McGill Quality of Life (MQOL) Questionnaire, and Karnofsky Performance Scale were administered at two-week intervals to 102 patients in a home palliative program. Outcomes in the sample and a regional palliative database (n=3,096) were analyzed. Cancer was the diagnosis in 96% of patients enrolled. Prevalence (P=0.0091) and severity of fatigue (P<0.001) were higher in women at entry and in a repeated measures analysis over time (severity, P=0.0048). Performance status did not explain this difference. MQOL scores were inversely correlated to fatigue (Spearman coefficient=-0.48, P<0.0001), but did not differ by sex. There was no difference in fatigue interference with MQOL in women and men. Although depression was higher in women (P=0.042) and related to fatigue at entry, it did not explain the sex difference in fatigue scores. Of the sociodemographic variables examined, neither education nor living situation contributed to the fatigue difference. This study shows a sex effect in the fatigue experienced by patients with advanced illnesses, which is not explained by baseline differences in performance, depression, MQOL, education, or living situation. That fatigue interference with MQOL is the same for men and women suggests that higher fatigue scores in women reflect not only a difference in the dimension of fatigue severity, but are also relevant in relation to impact on QOL. Assessment of fatigue should include the dimension of QOL important for both women and men.