ABSTRACT Background & Aims The distinction of drug‐induced liver injury (DILI), drug‐induced autoimmune‐like hepatitis (DI‐ALH), and autoimmune hepatitis (AIH) can be challenging due to overlapping clinical characteristics. Recently, polyreactive immunoglobulin G (pIgG) was identified as a novel biomarker in AIH. This retrospective study aimed to evaluate the diagnostic accuracy of pIgG to distinguish between AIH, DI‐ALH, and DILI and thus identify patients in need of immunosuppression. Methods Samples from 120 patients (AIH = 81, DI‐ALH = 16, DILI = 23) were compared to a control group (non‐AIH‐non‐DILI‐liver disease = 596 and healthy controls = 190). Results No patient in the DILI‐group but 98% in the AIH‐ and 94% in the DI‐ALH‐group received immunosuppressive treatment. PIgG levels were significantly higher in the AIH‐group 1.9 normalised arbitrary units (nAU) compared to DILI (1.1 nAU, p < 0.001), non‐AIH‐non‐DILI‐LD (1.0 nAU, p < 0.001) and healthy controls (0.27 nAU, p < 0.001). PIgG levels for DI‐ALH (1.7nAU) were significantly higher compared to DILI ( p = 0.044) and non‐AIH‐non‐DILI‐LD and healthy controls (both p < 0.001). Highest AUC was seen for pIgG (0.818) compared to conventional autoantibodies. The overall accuracy of pIgG to distinguish AIH from DILI (74%) and liver injuries with and without the need for immunosuppression (73%) was like that of ANA (71%/73%) and SMA (74%/69%) at cut‐offs of ≥ 1/40. PIgG was positive in up to 79% of patients with AIH that were negative for a conventional autoantibody and was positive in 90% of DI‐ALH cases compared to 25% in DILI that were caused by the same drugs. Conclusions PIgG may complement current serologic tests to identify patients with liver injury in need of immunosuppressive treatment.