Background: Fatigue is highly prevalent after hematopoietic stem cell transplantation (HCT). It has been described as intense and may last for years following treatment. Objective: The aim of this study is to compare fatigue, physical activity, sleep, emotional distress, cognitive function, and biological measures in HCT survivors with persistent fatigue (n = 25) with age-and gender-matched healthy controls with occasional tiredness (n = 25). Methods: Data were collected using (a) objective, real-time assessments of physical activity and sleep over 7 days; (b) patient-reported fatigue assessments; (c) computerized objective testing of cognitive functioning; and (d) biological measures. Differences between groups were examined using multivariate analysis of variance. Results: Survivors of HCT reported increased physical (P <.001), mental (P <.001), and overall (P <.001) fatigue as well as increased anxiety (P <.05) and depression (P <.01) compared with healthy controls. Red blood cell (RBC) levels were significantly lower in HCT survivors (P <.001). Levels of RBC for both groups, however, were in the normal range. Tumor necrosis factor-! (P <.001) and interleukin-6 (P <.05) levels were significantly higher in HCT survivors. Conclusions: Persistent fatigue in HCT survivors compared with healthy controls with occasional tiredness is accompanied by increased anxiety and depression along with decreased RBC counts. Elevated tumor necrosis factor-alpha and interleukin-6 levels may be important biomarkers. Implications for Practice: This study provides preliminary support for the conceptualization of fatigue as existing on a continuum, with tiredness anchoring one end and exhaustion the other. Persistent fatigue experienced by HCT survivors is more severe than the occasional tiredness of everyday life.