Background Osimertinib is the most promising treatment option for patients with epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) with acquired T790M resistance. However, recent studies have suggested that osimertinib could increase the frequency of serious adverse events (AEs) if administered immediately after immune checkpoint inhibitor (ICI) treatment. Methods In this single‐institution retrospective study conducted from May 2016 to January 2019, osimertinib was administered to 47 patients with pretreated advanced NSCLC harboring the EGFR mutation. Results Of the 47 patients, 20 (42.6%) were men and 27 (57.4%) were women. The median age was 71 years (range 37–83 years). A total of 19 patients (40.4%) had a smoking history. Furthermore, seven patients (14.9%) received osimertinib immediately after nivolumab therapy, while 40 patients (85.1%) were treated with osimertinib after treatment with drugs other than nivolumab. The frequency of grade 3 or 4 hepatotoxicity was significantly higher in patients with nivolumab prior to osimertinib (4/7; 57.1%) than in those treated with drugs other than nivolumab prior to osimertinib (2/40; 5.0%) (P = 0.0026). Liver biopsies were performed in two patients who received osimertinib immediately after nivolumab. In both patients, CD‐8‐positive T cell infiltration was predominantly observed in the liver tissues. Conclusions The use of osimertinib immediately after nivolumab significantly increased the frequency of grade 3 or higher hepatotoxicity in patients with advanced NSCLC harboring EGFR mutation acquired T790M resistance.