This study investigates complement activation and cellular inflammation in Fabry disease (FD) patients despite enzyme replacement therapy (ERT). FD is caused by mutations in the GLA gene, leading to the accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, lyso-Gb3. ERT with agalsidase-alfa or -beta is a main treatment option that reduces Gb3 levels. However, the study found that despite ERT, FD patients exhibit strong complement activation, as evidenced by elevated serum levels of C3a and C5a, which are anaphylatoxins involved in inflammation. The study analyzed 24 treatment-naïve FD patients and 18 healthy controls. It found that FD patients, particularly those with nonsense mutations, had significantly higher C3a and C5a levels compared to healthy controls. These levels remained elevated even after ERT, suggesting that complement activation is not effectively reduced by ERT. Additionally, patients with nonsense mutations were more likely to develop anti-drug antibodies (ADAs), which may contribute to persistent inflammation. The study also found increased levels of pro-inflammatory cytokines such as IL-6, IL-10, and TGF-β1 in FD patients, with the most significant increases observed in those with missense mutations. These cytokines may contribute to kidney damage, as evidenced by reduced estimated glomerular filtration rate (eGFR) in some patients. The findings suggest that complement activation and cytokine production may drive organ damage in FD, even in the presence of ERT. This highlights the need for additional therapeutic strategies targeting complement activation and inflammation to manage FD effectively. The study underscores the importance of understanding the complex interplay between complement activation, cytokine production, and organ damage in FD.This study investigates complement activation and cellular inflammation in Fabry disease (FD) patients despite enzyme replacement therapy (ERT). FD is caused by mutations in the GLA gene, leading to the accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, lyso-Gb3. ERT with agalsidase-alfa or -beta is a main treatment option that reduces Gb3 levels. However, the study found that despite ERT, FD patients exhibit strong complement activation, as evidenced by elevated serum levels of C3a and C5a, which are anaphylatoxins involved in inflammation. The study analyzed 24 treatment-naïve FD patients and 18 healthy controls. It found that FD patients, particularly those with nonsense mutations, had significantly higher C3a and C5a levels compared to healthy controls. These levels remained elevated even after ERT, suggesting that complement activation is not effectively reduced by ERT. Additionally, patients with nonsense mutations were more likely to develop anti-drug antibodies (ADAs), which may contribute to persistent inflammation. The study also found increased levels of pro-inflammatory cytokines such as IL-6, IL-10, and TGF-β1 in FD patients, with the most significant increases observed in those with missense mutations. These cytokines may contribute to kidney damage, as evidenced by reduced estimated glomerular filtration rate (eGFR) in some patients. The findings suggest that complement activation and cytokine production may drive organ damage in FD, even in the presence of ERT. This highlights the need for additional therapeutic strategies targeting complement activation and inflammation to manage FD effectively. The study underscores the importance of understanding the complex interplay between complement activation, cytokine production, and organ damage in FD.