In patients with paroxysmal nocturnal hemoglobinuria (PNH), complement component 5 (C5) inhibitors ravulizumab and eculizumab control terminal complement activity and intravascular hemolysis, drivers of morbidity and mortality. During C5 inhibitor treatment, ongoing C3 fragment deposition on surviving PNH red blood cells may cause clinically significant extravascular hemolysis (csEVH) in some patients. csEVH is not thought to be life-threatening but may cause symptomatic anemia and need for transfusion. This post-hoc analysis of studies 301 (NCT02946463) and 302 (NCT03056040) evaluated the prevalence of csEVH (symptomatic anemia [hemoglobin levels < 9.5 g/dL] with absolute reticulocyte count ≥ 120 × 109/L) in adult patients with PNH treated with ravulizumab or eculizumab for 6 months (183 days). The association between csEVH and fatigue (measured using the Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] scale) was also evaluated in study 302 patients with stable disease. On Day 183 of studies 301 and 302, respectively, csEVH prevalence was 23.2% (29/125) and 20.2% (19/94) with ravulizumab, and 24.8% (30/121) and 21.3% (20/94) with eculizumab. All patients in study 302 with csEVH experienced fatigue, which was mostly mild (ravulizumab: 79%, eculizumab: 65%) or moderate (ravulizumab: 21%, eculizumab: 30%). FACIT-F scores remained stable from baseline (ravulizumab: 42.2; eculizumab: 38.3) to Day 183 (ravulizumab: 44.3; eculizumab: 38.3); close to general population normative values. This analysis demonstrated that csEVH affected 20-25% of patients with PNH, most of whom experienced mild fatigue, with fatigue remaining stable during treatment. Ravulizumab and eculizumab continue to provide benefit to adults with PNH with csEVH.