Acute liver injury in patients with ARDS decreases survival but early stages may be easily missed due to the lack of sufficient biomarkers signalling its onset. Accordingly, we tested in ARDS patients the hypotheses that microRNA-122, the foremost liver-related microRNA (miR), 1) is an sensitive and specific early predictor for potential liver injury and 2) analysed its impact on 30-day-survival. We collected clinical data and analysed blood samples from 119 ARDS patients within the first 24 h of ICU admission and from 20 patients undergoing elective abdominal non-liver surgery serving as controls. Total circulating miR was isolated from serum and relative miR-122 expression was measured (using specific probes and spiked-in miR-54), as were liver function and 30-day survival. Acute liver injury was defined as a total bilirubin concentration ≥ 3.0 mg/dl, an ALT activity ≥350 U/l, and an INR ≥2.0. 30-day survival of the entire ARDS-cohort was 69% but differed between patients with normal liver function (77%) and acute liver injury (19% p <  0.001). miR-122 expression was 20fold higher in non-survivors (95%-CI 0.0149-0.0768; p = 0.001) and almost 4fold greater in survivors (95%-CI: 0.0037-0.0122; p = 0.005) compared to controls (95%-CI 0.0008-0.0034) and correlated with markers of liver cell integrity/function [ALT (p <  0.001, r = 0.495), AST (p <  0.001, r = 0.537), total bilirubin (p = 0.025, r = 0.206), INR (p = 0.001, r = 0.308), and GLDH (p <  0.001, r = 0.489)]. miR-122 serum expression discriminated survivors and non-survivors (AUC: 0.78) better than total bilirubin concentration (AUC: 0.66). Multivariable Cox-regression analysis revealed both acute liver injury (HR 7.6, 95%-CI 2.9-19.8, p <  0.001) and miR-122 (HR 4.4, 95%-CI 1.2-16.1, p = 0.02) as independent prognostic factors for 30-day mortality. Increased miR-122 serum expression is an early and independent risk factor for 30-day mortality in ARDS patients and potentially reveal an acute liver injury earlier than the conventional markers of liver cell integrity.