Although allogeneic hematopoietic stem cell transplantation (HSCT) features severe physical and psychological strain, no previous study has prospectively investigated fatigue beyond 3 years after transplantation. We investigated the temporal course of fatigue over 5 years, compared patients with the general population (GP) and tested for treatment- and complication-related risk factors. Patients were assessed before conditioning (T0, N = 239) and at 100-day (T1, N = 150), 1-year (T2, N = 102) and 5-year (T3, N = 45) follow-up. We measured fatigue with the Multidimensional Fatigue Inventory-20. Patients were compared with the GP at T0 and at T3. Global fatigue increased from T0 to T1 (t = 3.85, P<0.001), decreased from T1 to T2 (t = -2. 92, P = 0.004) and then remained stable (t = 0.45, P = 0.656). No difference in global fatigue was found between T0 and T3 (t = 0.68, P = 0.497). Compared with the GP, patients showed higher global fatigue at T0 (t = - 6.02, P< 0.001) and T3 (t = -2.50, P = 0.014). These differences reached meaningful effect sizes (d≥0.5). Acute and chronic GvHD predicted global fatigue at T1 (γ=0.34, P = 0.006) and T2 (γ = 0.38, P = 0.010), respectively. To conclude, fatigue among allogeneic HSCT patients improves with time, finally returning to pretransplantation levels. However, even after 5 years, the difference from the GP remains relevant. Patients with GvHD are at risk for increased fatigue.