Abstract: Objective To analyze the risk factors of drug-induced liver injury (DILI) in patients with newly treated pulmonary tuberculosis and to predict the risks associated with DILI during anti-tuberculosis therapy. Methods A total of 522 patients who were newly diagnosed with pulmonary tuberculosis and treated at Department of Infectious Diseases, Taicang First People’s Hospital from January 2015 to December 2024 were enrolled and their clinical data were retrospectively analyzed. According to whether DILI occurred during the course of anti-tuberculosis treatment, the patients were divided into a liver injury group and a non-liver injury group. Baseline characteristics and the time distribution of DILI occurrence were compared between the two groups. Univariate and multivariate Cox proportional hazards models were used to identify risk factors associated with DILI during anti-tuberculosis therapy and to construct a risk prediction model. The predictive performance of the model for DILI occurrence at different time points was evaluated using receiver operating characteristic (ROC) curves. Results Among the 522 patients, 75 developed DILI, with an incidence rate of 14.23%. Compared with the non-liver injury group, patients in the liver injury group were older and had lower albumin (ALB) levels and higher alanine aminotransferase (ALT) levels. DILI mainly occurred between weeks 4 and 8 after initiation of anti-tuberculosis treatment. Univariate Cox regression analysis showed that age, alcohol consumption, decreased red blood cell count, decreased hemoglobin level, decreased ALB, and elevated ALT were risk factors for DILI. Multivariate Cox regression analysis revealed that age (HR=1.028, 95%CI: 1.013-1.044, P<0.001), decreased ALB (HR=0.949, 95% CI: 0.902-0.998, P=0.042), and elevated ALT (HR=1.018, 95%CI: 1.003-1.033, P=0.011) were independent risk factors for DILI during anti-tuberculosis therapy. Patients with ALT≥20 U/L had a 1.713-fold risk of developing DILI compared with those with ALT<20 U/L (HR=1.713,95%CI: 1.072-2.737, P=0.024). A Cox regression model constructed using age, ALB, and ALT as predictors showed good predictive performance for DILI occurrence at weeks 4, 8, and 12 of anti-tuberculosis therapy and during the whole process. Conclusions Anti-tuberculosis DILI mainly occurs between weeks 4 and 8 after initiation of treatment. Advanced age, decreased ALB, and elevated ALT are important risk factors for DILI. The combined prediction model based on these variables shows good predictive value for DILI during anti-tuberculosis therapy.