Background: Fatigue and psychological distress are fairly common among nursing personnel,but their relationship is not clearly understood.Methods: In this cross-sectional study, we investigated the relationships between dimensions of fatigue and psychological distress among 699 public hospital nurses in Iran. The Multidimensional Fatigue Inventory (MFI–20) and General Health Questionnaire (GHQ–12)were used for evaluation of fatigue and psychological distress, respectively.Results: The total fatigue score of the MFI–20 was 52.5 (SD = 11.8). The general fatigue (mean± SD = 13.2±3.1) and reduced motivation (mean ± SD = 9.2±2.7) were the fatigue dimensions with the highest and lowest mean scores, respectively. The percentage of psychological distress(e.g., those nurses scored above the cut-off point [GHQ–12 ≥ 4]) was 29.1%. Stepwise multiple linear regression analysis indicated that general (P<0.001), physical (P<0.001) and mental(P<0.001) aspects of fatigue were significantly related to the psychological distress, so that the scores of these fatigue dimensions were significantly higher for those nurses with a higher level of psychological distress (above the cut-off point) than those with a lower level of psychological distress (below the cut-off point).Conclusion: The results emphasize the need for multi-component interventions aimed at decreasing both mental and physical fatigue, and consequently reducing the psychological distress among this group of healthcare professionals.