Fatigue is a prominent and poorly understood symptom of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to determine whether fatigue correlated with immune biomarkers and prognosis.In patients with HFrEF (N = 59) and healthy controls (N = 25), we prospectively measured fatigue (Profile of Mood States), depressive symptoms (Patient Health Questionnaire-8), sleep quality (Pittsburgh Sleep Quality Index), and immune biomarkers (plasma C-reactive protein [CRP], tumor necrosis factor-α [TNFα], and interleukins [IL-6 and IL-10]). Seattle Heart Failure Model (SHFM) mortality risk scores were determined. Patients with HFrEF had significantly greater fatigue and depressive symptoms and poorer sleep quality compared to control subjects. When controlling for depressive symptoms, however, fatigue did not differ significantly between patients with HFrEF and controls. Patients with HFrEF had significantly lower levels of IL-10 compared to controls. Cytokines did not correlate significantly with fatigue, but fatigue was significantly associated with higher SHFM scores.Depressive symptoms were an important covariate of fatigue in patients with HFrEF. Our study findings were the first to show a positive association between fatigue and the SHFM score, indicating that fatigue was associated with poorer prognosis.