Background: Fatigue after liver transplantation (LTx) is a major problem that is associated with lower daily functioning and health-related quality of life (HRQoL). This study aimed to assess changes over time in fatigue following LTx. We also examined daily functioning and HRQoL changes over time and assessed the influence of fatigue and changes in fatigue on daily functioning and HRQoL. We determined whether sleep quality, anxiety, and depression were associated with fatigue. Methods: We identified 70 LTx recipients who had previously participated in a cross-sectional study and reassessed them after two yr to determine changes in level of fatigue, daily functioning, and HRQoL. We also assessed sleep quality, anxiety, and depression after two yr. Results: Level of fatigue and level of daily functioning were unchanged at follow-up. HRQoL domains remained stable or worsened. Fatigue was a significant predictor of daily functioning and all HRQoL domains (p < 0.01). Change in fatigue was a significant predictor of daily functioning and the HRQoL domains of "physical functioning,'' "vitality,'' and "pain'' (p < 0.05). Sleep quality, anxiety, and depression were associated with fatigue severity (r = 0.35 to r = 0.60, p < 0.05). Conclusion: This longitudinal study shows that fatigue is a chronic problem after LTx and that daily functioning and HRQoL do not improve over time. This study supports the need for intervention programs to address fatigue after LTx.