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The prognostic role of high-sensitivity C-reactive protein (hsCRP) in acute heart failure is less well established than for chronic heart failure and the impact of its variation is unknown. We studied the impact of hsCRP variation in acute heart failure and whether it differed according to left ventricular function.We analyzed patients prospectively included in an acute heart failure registry. Admission and discharge hsCRP were evaluated as part of the registry's protocol and its relative variation (ΔhsCRP) was assessed. ΔhsCRP during hospitalization = [(admission hsCRP – discharge hsCRP)/admission hsCRP] × 100. Endpoint: all-cause death; follow-up: 3 years. A multivariate Cox-regression model was used to assess the prognostic value of ΔhsCRP (continuous and categorical variable: cut-off 40% decrease); analysis was stratified according to ventricular function.We studied 439 patients: mean age 75 years, 50.1% men and 69.2% had heart failure with reduced ejection fraction (HFrEF). Median discharge hsCRP was 12.4 mg/l and median ΔhsCRP was ∼40%. During follow-up 247 patients (56.3%) died: 73 (54.1%) heart failure with preserved ejection fraction (HFpEF) patients and 174 (57.2%) HFrEF patients. The multivariate-adjusted hazard ratio of 3-year mortality in HFpEF patients with hsCRP decrease of at least 40% during hospitalization was 0.56 (95% CI 0.32–0.99). A decrease of at least 40% in hsCRP was not mortality-associated in HFrEF patients. There was interaction between ΔhsCRP and left ventricular ejection fraction.A decrease of at least 40% in hsCRP in acute heart failure was associated with a 44% decrease in 3-year death risk in HFpEF patients. No association between ΔhsCRP and prognosis existed in HFrEF patients. Inflammation appears to play a different role according to left ventricular function.