We have evaluated risk factors associated with fatigue in 220 cancer patients during hospitalization for stem-cell transplantation (SCT). Fatigue was assessed using a validated one-item energy scale and a comprehensive set of fatigue predictors, at hospital admission (baseline), day of SCT, and 7 days and 14 days after SCT. In cross-sectional multivariate analysis, depression was the variable most consistently and strongly associated with fatigue; other factors significantly associated with fatigue at some time during the study included older age, higher education, smoking, lower Karnofsky performance status, loss of appetite, nausea/vomiting, pain, higher regimen-related toxicity, low hemoglobin level, requirement for red blood-cell transfusions, and third year of the study period. In prospective multivariate analysis, baseline depression showed significance or a trend towards significance in its ability to predict subsequent measures of fatigue during hospitalization. Our findings may help to shed light on the mechanisms underlying fatigue and may also guide future interventions.