Background: To date, definitions of liver dysfunction (LD) after hepatic resection rely on late postoperative time points. Further, the used parameters are markedly influenced by perioperative management. Thus, we aimed to establish a very early postoperative score to predict postoperative mortality. Methods: Liver related parameters were evaluated after liver resection in a retrospective evaluation cohort of 228 colorectal cancer patients with liver metastasis (mCRC) and subsequent validation in a prospective set of 482 consecutive patients from 4 independent institutions undergoing hepatic resection was performed. Results: C-reactive protein (CRP, AUC =0.739, P<0.001) and antithrombinⅢ-activity (ATⅢ, AUC=0.844, P<0.001) on the first postoperative day (POD) were found to be elevated in patients with LD. Cut-off values for CRP at 3 mg/dL and for ATⅢ at 60％ significantly identified high-risk patients for postoperative LD and mortality (P<0.001) and thus defined the 3-60 criteria on POD1. The 3-60 criteria showed superior sensitivity and specificity compared to established criteria for LD [3-60 criteria: total positive patients: 26 patients (70％ mortality detected), odds ratio (OR): 48.8; Inteational Study Group for Liver Surgery: total positive patients: 43 (70％ mortality detected), OR: 23.3; Peak7: total positive patients:9 (30％ mortality detected), OR: 27.8; 50-50: total positive patients: 9 (30％ mortality detected), OR: 27.8]. These results could be validated in a multi-center analysis and ultimately the 3-60 criteria remained an independent predictor of postoperative mortality upon multivariable analysis. Conclusions: The 3-60 criteria on POD1 predict postoperative LD and mortality early after liver resection with a comparable or better accuracy than established criteria, allowing for immediate identification of high-risk patients.