Objectives: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, non‐malignant haematological disorder associated with disabling fatigue and reduced health‐related quality of life. Post hoc analysis of PEGASUS phase 3 trial (NCT03500549) characterised improvements in patient‐reported fatigue measured by functional assessment of chronic illness therapy‐fatigue (FACIT‐fatigue) instrument item‐level ratings for pegcetacoplan and eculizumab for the treatment of PNH. Methods: Item‐level responder analysis was conducted on a ≥2‐level change from baseline (CFB) clinically important response (CIR) for the FACIT‐fatigue 13 individual items rated on a 5‐level Likert scale. We evaluated ≥2‐level change against the minimal clinically important difference (MCID) of the FACIT‐fatigue total score (≥5 points) and clinical parameters, haemoglobin (Hb; ≥1 g/dL) and normalised absolute reticulocyte count (ARC; 30–100 pg/cells). Logistic regressions estimated baseline‐to‐Week‐16 FACIT‐fatigue item‐level transitional probabilities; Kaplan–Meier analysis estimated time to FACIT‐fatigue item CIR. Results: Pegcetacoplan versus eculizumab was associated with significantly greater odds of Week 16 CIR across 8/13 items and on total score MCID (OR [CI] = 11.19 [3.73, 33.57]) and faster times to responses. The item‐level CIR threshold also showed clinical relevance on Hb level and ARC normalization. Conclusions: Compared with eculizumab, pegcetacoplan was associated with clinically meaningful greater improvements on a majority of FACIT‐fatigue items. [ABSTRACT FROM AUTHOR]