BACKGROUND: The relationship between congestion and inflammation in heart failure is a challenging issue. We sought to evaluate the relationship between congestion and inflammation in acute heart failure (AHF) and the impact of therapies on it. METHODS: We enrolled 124 patients with AHF (79 ± 10 years, 52% men). Brain natriuretic peptide (BNP), abdominal and peripheral congestion by (intra-abdominal pressure [IAP] and bioimpedance vector analysis (Hydration Index, HI, %)], and systemic inflammation by mean of high-sensitivity C-Reactive Protein (hs- CRP) were assessed both at admission and discharge. RESULTS: hs-CRP levels at admission (median values of 11.9 mg/L) correlated with HI (r=0.22; P<0.02). hs- CRP higher than 7.1 mg/L predicted HI with a positive predictive value of 39% and negative predictive value of 91% (AUC=0.70). hs-CRP level reduction was higher in those with severe peripheral congestion (HI: 66%, 95%CI 38-76). The modifications in hs-CRP levels were significantly correlated to HI variations (r=0.31; P<0.001), but not to BNP and IAP variations. After intravenous administration of loop diuretics (mean duration: 7 days, 95% CI 6-8), BNP, HI, hs-CPR, and IAP values significantly decreased: -43% (95% CI 37-51), – 4.6 % (95% CI: 3.1-5.7), -34% (95% CI: 4-48), and -15% (95% CI: 9-18), respectively. Nevertheless, the impact on the relationship between hs-CRP and congestion was independent from loop diuretics at multivariate analysis. CONCLUSIONS: Systemic inflammation was associated with severe peripheral congestion although this relationship seemed not to be influenced by the administration of loop diuretics. This finding suggests that peripheral interstitial fluid accumulation is a source of immune activation and loop diuretics did not influence such a correlation.