A 66-year-old man was diagnosed with driver mutation in wild-type lung adenocarcinoma (clinical stage IVB, T4N3M1c BRA, OTH) with a tumor proportion score for programmed death ligand 1 expression of 70%–80%. After receiving radiation therapy for brain metastasis with oral steroids and trimethoprim-sulfamethoxazole (TMP-SMX), the patient received pembrolizumab as first-line treatment. Soon after, the patient developed hepatitis that did not improve after TMP-SMX withdrawal. On diagnosis of pembrolizumab-induced hepatitis, the patient was treated with 50mg/day prednisolone for two weeks and transaminase levels returned to normal. Prednisolone was decreased to 40mg/day and TMP-SMX was restarted. A few hours later, the patient developed fever and re-elevation of transaminases. By increasing prednisolone to 100mg/day and adding mycophenolate mofetil, his hepatitis gradually improved; however, the patient died on day 98 because of the progression of lung cancer. An autopsy revealed drug-induced hepatocellular injury. Severe pembrolizumab-induced hepatitis is rare. In this patient, under unrestrained T cell activation with pembrolizumab, an allergic reaction to TMP-SMX which involves T cells, may have worsened the hepatitis.