Background: Fibroblast growth factor-23 produced by osteocytes regulates calcium and phosphate homeostasis which are cornerstones for bone integrity. Recently, FGF23 was also found to be directly related with both severity and prognosis of heart failure. However, the mechanism of FGF23 regulation in heart failure, particularly in patients with preserved renal function is poorly understood. Methods: In this retrospective single center trial we assessed the association of systemic inflammation (surrogated by CRP) and FGF23 regulation in 221 stable non-ischemic heart failure patients (age ≥ 18) with reduced ejection fraction and an estimated glomerular filtration rate of more than 60 ml/min/1.73m². Furthermore, we analyzed the prognostic ability of FGF23 and CRP in this population. Fasting ct-FGF23, highly sensitive CRP and a comprehensive panel of further biomarkers, as well as invasive hemodynamic measures from right heart catheterization, were used for univariate and multivariate regression analysis. Results: In bivariate correlation analysis ct-FGF23 was correlated with Cardiac output (r= -0.42); NTproBNP (r=0.34) and CRP (r=0.31); for all of those p < 0.001. Multivariate linear regression analysis revealed CRP and CO as independently associated with ct-FGF23 (total model fit; r²=0.32; p <0.001). In time to event analysis ct-FGF23 was the only independent parameter predicting transplant-free survival. Conclusion: Our data indicate an association of systemic inflammation and FGF23 in heart failure independent from renal function and supports the hypothesis that FGF23 may be directly involved in heart failure.