Here we report a PNH patient with incomplete responses to eculizumab and pegcetacoplan, carrying a heterozygous C3 gain-of-function (GOF) mutation (c.1514G>A; p.Arg505His) that reduces pegcetacoplan binding and impairs C3b inactivation by FH, thereby dysregulating the alternative pathway and increasing E-PNH opsonization. Here, C3 is linked to paroxysmal nocturnal hemoglobinuria.