Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 DILI patients enrolled into the Spanish DILI Registry over a 20-year time period.Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome were collected.843 cases enrolled up to 2018 had a mean age of 54 years (48% females). Hepatocellular injury was associated with younger age (aOR per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives was the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p=0.0083) and in patients with underlying liver disease (p=0.0221). Independent predictors of liver-related death/transplantation outcome included nR-based hepatocellular injury, female sex, higher onset AST and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).AST elevation at onset is a strong predictor of poor outcome and should be performed routinely in DILI evaluation. Older DILI patients with hepatocellular damage and patients with underlying hepatic conditions have higher mortality. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and outcome risk factors in DILI and can aid physicians in DILI characterization and management.