To clarify high-risk factors and develop a novel nomogram model to predict biochemical resolution (BR) or not (BNR) in patients with chronic drug-induced liver injury (DILI).Retrospectively, 3,655 out of 5,326 patients with chronic DILI were enrolled from 9 participating hospitals, of whom 2,866 underwent liver biopsy. All these patients were followed up for over one year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5×upper limit of normal (ULN) or alkaline phosphatase (ALP) >1.1×ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707/3,655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (P < 0.001). Biochemically, AST and total bilirubin, platelets, prothrombin time, sex and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a C-index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort.Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.This article is protected by copyright. All rights reserved.