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Background: The aim of this study was to determine factors associated with the severity of cancer related fatigue (CRF) and predictors of improvement of CRF at the first follow-up visit in patients with advanced cancer referred to outpatient palliative care clinic (OPC). Methods: We reviewed the records of consecutive patients with advanced cancer presenting to OPC. Edmonton Symptom Assessment System (ESAS) scores were obtained at the initial and subsequent visits between January 2003 and December 2008. All patients received interdisciplinary care led by palliative medicine specialists following an institutional protocol. Fatigue improvement was defined as a reduction of ≥2 points in ESAS score relative to the baseline. Descriptive statistics were used to summarize patient characterstics. Univariate analyses were performed and only significant variables were included in multivariate regression analysis to determine factors associated with severity and improvement in CRF. Results: A total of 1778 evaluable patients were analyzed (median age, 59 years; 52% male). The median time between visits was 15 days. Median fatigue scores on the ESAS were 6 at baseline and 5 at follow-up. Severity of all ESAS items and low serum albumin were associated with fatigue at baseline (p < 0.0001). The improvement of fatigue was observed in 586 patients (33%). The hierarchical model showed that fatigue improved over time (b = −0.009; p = 0.0009). low appetite (odds ratio [OR] = 1.09 per point; p = 0.0113) and genitourinary cancer (OR = 1.74 per point; p = 0.0458) were significantly associated with improvement of fatigue. Conclusions: CRF is strongly associated with physical and emotional symptoms. Genitourinary cancer and low appetite at baseline were associated with successful improvement of fatigue. [ABSTRACT FROM AUTHOR]