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Background Activation of Kupffer cells may be involved in the pathogenesis of portal hypertension by release of vasoconstrictive substances and fibrosis due to co-activation of hepatic stellate cells. Aim To study soluble plasma (s) CD163, a specific marker of activated macrophages, as a biomarker for portal hypertension in patients with liver cirrhosis. Methods We measured sCD163 concentration and the hepatic venous pressure gradient ( HVPG) by liver vein catheterisation in 81 cirrhosis patients ( Child- Pugh CP- A: n = 26, CP- B: n = 29, CP- C: n = 26) and 22 healthy subjects. We also measured their cardiac output ( CO), cardiac index and systemic vascular resistance ( SVR). Liver status was examined by Child- Pugh and MELD-score. Results In cirrhosis, sCD163 concentration was nearly three times higher than in controls (4.7 ± 2.5 vs. 1.6 ± 0.5 mg/L, P < 0.001). sCD163 was also higher, as measured in steps by CP-score ( P < 0.001). The HVPG rose steeply to an asymptote of 22 mmHg with sCD163 up to about 5 mg/L and not to higher values with higher sCD163. In a multivariate analysis, sCD163 was the only independent predictor of the HVPG but did not predict any of the systemic circulatory findings. sCD163 > 3.95 mg/L (upper normal limit) predicted HVPG ≥ 10 mmHg with a positive predictive value of 0.99. Conclusions Circulating sCD163 originating from activated Kupffer cells is increased in cirrhosis with increasing Child- Pugh score and with increasing HVPG, and it is an independent predictor for HVPG. These findings support a primary role of macrophage activation in portal hypertension, and may indicate a target for biological intervention. [ABSTRACT FROM AUTHOR]