IgG4-related disease is a systemic disorder involving a spectrum of multiple indications, and various histopathological features are shared among different IgG4-related disease subtypes, which challenge diagnosis, although certain syndromes have organ-specific involvement. Among them, Mikulicz's disease affecting the salivary and lacrimal glands, distinguished by often elevated levels of serum IgG4, infiltration of IgG4+ plasma cells into target tissues, and diffuse swelling, mass formation, or fibrosis of affected organs. However, there are several diseases, which could manifest as salivary gland swelling, mimicking Mikulicz's disease, such as Sjogren's syndrome, mumps virus infection, obstruction of parotid duct, non-Hodgkin's lymphoma (NHL), and so on. So differential diagnosis is important and essential as to the salivary gland swelling. In this paper, we analyzed a case of a 59-year-old male with symmetric salivary gland swelling. Mikulicz's disease was misdiagnosed at the beginning without biopsy. Prednisone treatment ever seemed to be effective and antibiotics had no effect. Besides salivary involvement, the patient also manifested as testicle swelling and severe pancytopenia with the development of the disease, which rarely appeared in Mikulicz's disease. Physical examination showed skin, sclera yellow dye, swollen submandibular, sublingual and lacrimal gland and splenomegaly. As a result, biopsy of right submandibular gland was made, and mucosa-associated lymphoid tissue lymphoma was confirmed by morphology and immunohistochemistry. Bone marrow biopsy also confirmed that lymphoma cells were found in the bone marrow. Finally, the diagnosis of mucosa-associated lymphoid tissue lymphoma (Phase IVE, Group A) was made on the patient, who was transferred to the hematology department for the treatment. NHL, especially, primary extranodal lymphoma usually involves the salivary gland, and painless swelling of the salivary gland is a common manifestation, similar with Mikulicz's disease. So although salivary gland swelling is often associated with autoimmune diseases such as Sjogren's syndrome and IgG4-related disease, the awareness and suspicion of a possibility of NHL are essential for rheumatologists. Biopsy is a necessary examination to decrease or avoid misdiagnosis.