Drug-induced liver injury has been associated with various antipsychotic drugs. Comparative studies between individual antipsychotic drugs are largely not available. Antipsychotic drug utilization data and reports of severe antipsychotic drug-induced liver injury were assessed by using data from an observational pharmacovigilance programme – Arzneimittelsicherheit in der Psychiatrie (AMSP) – during the period 1993-2016. Of the 333,175 patients treated with antipsychotic drugs, a total of 246 (0.07%) events of severe drug-induced liver injury were identified. Phenothiazines were associated with significantly higher rates of severe drug-induced liver injury (0.03%, 95% CI =0.02-0.04) than thioxanthenes (0.01%, 95% CI =0.00-0.02) or butyrophenones (0.01%, 95% CI =0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI =0.10-0.16), perazine (0.09%, 95% CI =0.05-0.15), and clozapine (0.09%, 95% CI =0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more antipsychotic drugs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe drug-induced liver injury while older patients (≥65 years old) were significantly less often affected. In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual antipsychotic drugs associated with severe drug-induced liver injury.