ABSTRACT: There is limited information about the effects of corticosteroids on severe drug-induced liver injury (DILI). This study aimed to investigate the efficacy and safety of prednisone in severe DILI.Ninety patients with severe DILI were enrolled and studied retrospectively. They were divided into prednisone (n?=?66) and control groups (n?=?24), undergoing the same treatment regimen except that patients in the prednisone group received a median daily dose of 40?mg prednisone. The primary endpoint was severity reduction (serum total bilirubin [TBIL] <86??mol/L).During the study, the cumulative rates of severity reduction at 4-, 8-, and 12 days were comparable between the 2 groups (prednisone versus control: 7.6%, 33.3%, and 60.6% versus 12.5%, 37.5%, and 66.7%, P?=?.331), and were markedly lower in the high-dose group than in the low-dose group (0%, 28.6%, and 35.7% versus 9.6%, 34.6%, and 67.3%, P?=?.012) or in the control group (0%, 28.6%, and 35.7% versus 12.5%, 37.5%, and 66.7%, P?=?.023). The 30-day overall survival rate in the prednisone group was significantly higher than in the control group (100% versus 91.7%, P?=?.018). Serum bilirubin and transaminase values gradually decreased in both groups, which were not significantly different mostly. Cox-regression models revealed that baseline TBIL (hazard ratio: 0.235; 95% confidence interval: 0.084-0.665; P?=?.006) was the only predictor for severity reduction. No severe adverse event was noted in both groups.Prednisone therapy is safe but not beneficial, and even detrimental at a daily dose > 40?mg for the treatment of severe DILI.