A 28-year-old woman with untreated autoimmune disorder, demonstrated skin rash and fever after taking Amoxicillin-clavulanate and developed progressive jaundice. A bone marrow aspiration indicated an increased number of macrophages with hemophagocytosis and liver biopsy showed pure centrilobular cholestasis with necrosis and some absence of portal bile ducts. Furthermore, a serological test for Epstein-Barr virus was positive. Under treatment by liver dialysis and administration of steroids led to rapidly defervescence and clinical improvement. However, liver enzymes were still markedly elevated with persistent anemia, even after immunosuppressive treatment. The patient is currently waiting for liver transplantation. This is the first description of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis, with underlying causes including infection, drug-induced factors and untreated autoimmune disorder. A 28-year-old woman with untreated autoimmune disorder, demonstrated skin rash and fever after taking Amoxicillin-clavulanate and developed progressive jaundice. A bone marrow aspiration represented an increased number of macrophages with hemophagocytosis and liver biopsy showed pure centrilobular cholestasis with necrosis and some Under treatment by liver dialysis and administration of steroids led to rapidly defervescence and clinical improvement. However, liver enzymes were still markedly elevated with persistent anemia, even after immunosuppressive treatment. The is the first description of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis, with underlying causes including infection, drug-induced factors and untreated autoimmune disorder.