BACKGROUND: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF). METHODS: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders. RESULTS: Median FGF23 was 218.0 [IQR: 117.1-579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P<0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P<0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09-1.26) per log increase, P<0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08-1.22) per log increase, P<0.001). CONCLUSIONS: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization.