Background & Aims Patients with liver disease often show profound abnormalities in their haemostatic system. Studies using thrombin generation demonstrate rebalanced coagulation in patients with chronic liver disease. Our aim was to evaluate the haemostatic profile in patients with acute liver injury/failure (ALI/ALF) compared with healthy controls. Methods Thrombin generation was measured in the presence and absence of thrombomodulin (TM) to activate protein C (PC) with endogenous thrombin potential (ETP; the area under the thrombin generation curve) a key parameter. Routine coagulation assays were also performed. Results Thirty two patients with ALI/ALF and 40 controls were recruited. Patients had grossly abnormal coagulation profiles with decreased pro‐ and anticoagulant factors compared with controls (P < 0.001 for all comparisons), except for median Factor VIII which was increased 247 U/dl interquartile range: 214–347 in patients compared with 120 U/dl 97–139; P < 0.001 in controls. Mean ETP was significantly lower in patients 886 nM.min (± 436) compared with controls 1596 nM.min (± 259; P < 0.001). However, when the assay was repeated with TM to activate PC, there was no significant difference in mean ETP + TM between patients and controls (632 ± 418 vs 709 ± 301 nM.min respectively; P = 0.666). Furthermore, the ETP ratio (ETP + TM/ETP) was significantly higher in patients 0.89 (0.60–0.97) compared with controls 0.48 (0.3–0.6; P = 0.002) and negatively correlated with PC (R = −0.487, P = 0.003) and Factor V (R = −0.431, P = 0.01). Conclusion ALI/ALF patients have normal ETP in the presence of TM. This supports rebalanced coagulation mediated by acquired PC resistance because of the reduction in PC, Factor V and concomitant increase in Factor VIII.