Immunoglobulin type G4 -related disease (IgG4-RD) is known as a chronic systemic inflammatory disease, which is sometimes associated with lung cancer. However, the detailed association between IgG4-RD and lung cancer in clinical settings is still poorly understood. An 80-year-old man was diagnosed with progressive lung adenocarcinoma carrying an EGFR point mutation at L858R, and osimertinib treatment was administered. Two months later, although osimertinib treatment showed good response to the primary tumor, fever and anorexia appeared, and multiple lymph nodes, in particular in the left axillary, became swollen. Ultrasonography-guided biopsy of the axillary lymph node revealed infiltration of lymphocytes with IgG4-positive plasma cells and fibrosis. Serum IgG4 levels were also increased. These results suggested that the multiple swollen lymph nodes were not metastasis, but IgG4-related disease. Based on these results, therapy using prednisolone was initiated. Multiple lymphadenopathy gradually decreased, and his symptoms improved. Currently, his good responses to osimertinib treatment have been maintained. Like in our case, multiple lymphadenopathy with IgG4-positive plasma cell infiltration during successful anti-cancer treatment is quite rare. In this case, it was hypothesized that anti-cancer treatment with osimertinib induced IgG4-positive plasma cell infiltration in multiple lymph nodes. When lymphadenopathy occurs during lung cancer treatment, IgG4-RD has to be considered other than lung cancer metastasis.