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Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease (FD). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and healthy controls (n=40). Plasma levels of the following markers of inflammation and cardiac remodeling were determined: tumor necrosis factor (TNF), TNF receptor 1 (TNFR1) and 2 (TNFR2), interleukin‐6, matrix metalloprotease‐2 (MMP‐2), MMP‐8, MMP‐9, galectin‐1, galectin‐3, B‐type natriuretic peptide (BNP), midregional pro–atrial natriuretic peptide (MR‐proANP), and globotriaosylsphingosine. Clinical profile, cardiac magnetic resonance imaging, and echocardiogram were reviewed and correlated with biomarkers. Patients with FD had elevated plasma levels of BNP, MR‐proANP, MMP‐2, MMP‐9, TNF, TNFR1, TNFR2, interleukin‐6, galectin‐1, globotriaosylsphingosine, and analogues. Plasma TNFR2, TNF, interleukin‐6, MMP‐2, and globotriaosylsphingosine were elevated in FD patients with left ventricular hypertrophy, whereas diastolic dysfunction correlated with higher BNP, MR‐proANP, and MMP‐2 levels. Patients with late gadolinium enhancement on cardiac magnetic resonance imaging had greater levels of BNP, MR‐proANP, TNFR1, TNFR2, and MMP‐2. Plasma BNP, MR‐proANP, MMP‐2, MMP‐8, TNF, TNFR1, TNFR2, galectin‐1, and galectin‐3 were elevated in patients with renal dysfunction. Patients undergoing enzyme replacement therapy who have more severe disease had higher MMP‐2, TNF, TNFR1, TNFR2, and globotriaosylsphingosine analogue levels. Conclusions Inflammatory and cardiac remodeling biomarkers are elevated in FD patients and correlate with disease progression. These features are consistent with a phenotype dominated by heart failure with preserved ejection fraction and suggest a key pathogenic role of systemic inflammation in FD.