Multiple myeloma (MM) is a type of hematological malignancy that can affect all types of tissues in human. However, it is extremely rare that pleural effusion presents as the first sign in MM patients. A 54-year-old male patient attended our department of respiratory medicine complaining of shortness of breath for the past 3 months. A chest computer tomography (CT) radiograph revealed a bilateral pleural effusion, which was further assessed as exudative type. Sinus spiral CT scan demonstrated diffuse bone destruction of craniofacial bone. A broad reduction of the lumbar bone signal was confirmed by MRI. Furthermore, pleural biopsy showed abnormal proliferation of plasmocytes whereas bone marrow biopsy showed active hyperplasia of plasmacytoid cells. Interestingly, Bence-Jones protein in urine and serum protein electrophoresis was negative. The patient was diagnosed as non-secretory MM. He then underwent chemotherapy with vincristine, adriamycin and dexamethasone. Partial regression of the pleural effusion was achieved after two rounds of chemotherapy, and the patient has been followed for more than one year.