This study investigates complement activation and cellular inflammation in male patients with Fabry disease (FD) before and after enzyme replacement therapy (ERT). The authors found strong complement activation in 17 classical male FD patients with either missense or nonsense mutations, evidenced by high serum levels of C3a and C5a, even after ERT. Patients with nonsense mutations showed higher lyso-Gb3 levels and developed neutralizing anti-drug antibodies (ADAs), while those with missense mutations had heterogeneous C3a and C5a levels. Additionally, increased levels of IL-6, IL-10, and TGF-β1 were observed in FD patients, particularly in those with missense mutations, who also developed mild nephropathy. The findings suggest that complement activation, independent of lyso-Gb3 reduction, contributes to chronic inflammation and organ damage in FD, even with ERT. Targeting the complement system may be a potential therapeutic approach to reduce ongoing inflammation in FD.This study investigates complement activation and cellular inflammation in male patients with Fabry disease (FD) before and after enzyme replacement therapy (ERT). The authors found strong complement activation in 17 classical male FD patients with either missense or nonsense mutations, evidenced by high serum levels of C3a and C5a, even after ERT. Patients with nonsense mutations showed higher lyso-Gb3 levels and developed neutralizing anti-drug antibodies (ADAs), while those with missense mutations had heterogeneous C3a and C5a levels. Additionally, increased levels of IL-6, IL-10, and TGF-β1 were observed in FD patients, particularly in those with missense mutations, who also developed mild nephropathy. The findings suggest that complement activation, independent of lyso-Gb3 reduction, contributes to chronic inflammation and organ damage in FD, even with ERT. Targeting the complement system may be a potential therapeutic approach to reduce ongoing inflammation in FD.