Background Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS‐AKI) is a unique type of renal failure that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS‐AKI is lacking. Aim and Methods To characterize the systemic inflammatory response, as estimated by measuring a large number of cytokines, in 161 patients hospitalized for an acute decompensation of cirrhosis: 44 patients without acute kidney injury (AKI), 63 patients with hypovolaemia‐induced AKI and 58 patients with HRS‐AKI. Results HRS‐AKI was characterized by an altered cytokine profile compared to the other two groups, particularly IL‐6, IL‐8, TNF‐α, VCAM‐1, fractalkine and MIP‐1α. The inflammatory response was not related to presence of bacterial infection, concomitant acute‐on‐chronic liver failure or severity of renal dysfunction. Patients who responded to terlipressin and albumin had only a decrease in TNF‐α and RANTES after treatment without changes in other cytokines. Interestingly, patients with persistent HRS‐AKI had higher levels of IP‐10 and VCAM‐1 compared to those with resolution of HRS‐AKI. VCAM‐1 was also an independent predictor of 3‐month mortality. A systems biology analysis approach showed that the inflammatory status of HRS‐AKI was similar to that of chronic nonhepatic inflammatory conditions, such as lupus erythematosus or inflammatory bowel disease. Conclusion Hepatorenal syndrome is characterized by a marked systemic inflammatory state, reminiscent of that of nonhepatic inflammatory diseases, that correlates with patient outcomes. See Editorial on Page 1199