This study evaluates the effectiveness and safety of intensive pegcetacoplan treatment for managing acute breakthrough hemolysis (BTH) in patients with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan, a proximal complement C3 inhibitor, is effective in controlling both intravascular and extravascular hemolysis in PNH patients. The study analyzed 13 patients who experienced an acute BTH event and received either a single intravenous (IV) dose of 1080 mg or three consecutive subcutaneous (SC) doses of 1080 mg of pegcetacoplan. Lactate dehydrogenase (LDH) levels decreased significantly in most patients, with 69% achieving LDH levels below 2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were resolved by the investigators. The treatment was safe and well-tolerated, with no serious adverse events reported. The study supports the use of intensive IV or SC pegcetacoplan dosing for managing acute BTH events in PNH patients. The results suggest that intensive pegcetacoplan treatment is effective in reducing hemolysis and improving clinical outcomes in patients with PNH. The study also highlights the importance of monitoring for potential complement-amplifying conditions, such as infections or vaccinations, which may contribute to BTH events. The findings indicate that intensive pegcetacoplan treatment is a viable option for managing acute BTH in PNH patients. The study was registered at clinicaltrials.gov as NCT03531255.This study evaluates the effectiveness and safety of intensive pegcetacoplan treatment for managing acute breakthrough hemolysis (BTH) in patients with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan, a proximal complement C3 inhibitor, is effective in controlling both intravascular and extravascular hemolysis in PNH patients. The study analyzed 13 patients who experienced an acute BTH event and received either a single intravenous (IV) dose of 1080 mg or three consecutive subcutaneous (SC) doses of 1080 mg of pegcetacoplan. Lactate dehydrogenase (LDH) levels decreased significantly in most patients, with 69% achieving LDH levels below 2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were resolved by the investigators. The treatment was safe and well-tolerated, with no serious adverse events reported. The study supports the use of intensive IV or SC pegcetacoplan dosing for managing acute BTH events in PNH patients. The results suggest that intensive pegcetacoplan treatment is effective in reducing hemolysis and improving clinical outcomes in patients with PNH. The study also highlights the importance of monitoring for potential complement-amplifying conditions, such as infections or vaccinations, which may contribute to BTH events. The findings indicate that intensive pegcetacoplan treatment is a viable option for managing acute BTH in PNH patients. The study was registered at clinicaltrials.gov as NCT03531255.