OBJECTIVES: Terminal complement inhibitors can control intravascular hemolysis in Paroxysmal Nocturnal Hemoglobinuria (PNH) patients, although the hematological response achieved may not persist, and it may become unsatisfactory. The proximal (C3) complement inhibitor Pegcetacoplan (PEG) improves this situation in clinical trials, yet real-world data on its efficacy and safety are scarce. METHODS: This non-interventional, retrospective, multicenter study presents clinical and hematological data from the first PNH patients in Spain treated with PEG (n = 32, median 13 months, range 4-61). RESULTS: PEG rapidly increases the patient's hemoglobin (median increase of 2.65 g/dL in 4 weeks, > 2 g/dL increase in 56.3% of patients), reaching > 8, 10 and 12 g/dL in 93.7%, 87.5% and 46.9% of patients, respectively. Packed red blood cell transfusion requirements dropped from 62.5% to 15.6% of patients treated with PEG, and there was a fall in breakthrough hemolysis from 34.4% to 9.4% after 6 months of treatment. No thrombosis and only mild adverse events (n = 11 patients) were described with PEG therapy. Finally, physicians perceived important enhancements in patients' health-related quality of life. DISCUSSION: This real-world clinical data confirms that PEG produces significant and rapid improvements in hemoglobin and hemolytic parameters, with a favorable safety profile. The data extends that of earlier clinical trials and small real-world studies by offering a longitudinal (as opposed to cross-sectional) assessment of the patient responses across a large number of centers, following a variety of clinical practices.​​​​​. CONCLUSION: PEG treatment of patients with PNH produces significant and rapid improvements in hemoglobin and hemolytic parameters, with a favorable safety profile.