Background: Multiple myeloma (MM) is a hematologic malignancy of plasma cell origin. Multiple myeloma with pleural effusion (PE) is not uncommon. The existing literature on MM with PE in China and abroad is limited to case reports. Thus, it is necessary to investigate the characteristics of MM with PE and the associated prognosis to achieve early recognition and treatment.Method: Patients diagnosed with MM from January 2000 to December 2019 at Peking University Third Hospitals were assessed retrospectively. We summarized and analyzed the clinical manifestations, laboratory examinations, diagnosis and prognoses of patients by using clinical data and a literature review.Result: A total of 490 patients with MM were included. 272 patients (55.5%) had PE. Confirmed by pathology, there were 45 myelomatous pleural effusion (MPE) patients and 28 non-MPE patients. The total protein, albumin, calcium and complement C3 levels were lower and the β2-MG levels were higher in the PE group than in the non-PE group (P <0.05). Low total protein and low albumin levels were independent risk factors for PE. The levels of nucleated cells, total protein, LDH, and ADA were higher in the MPE group than the non-MPE group (P <0.05). There were no significant differences in the specific gravity or the levels of protein, glucose and CEA. Multivariate regression analysis suggested that low LDH levels and high levels of nucleated cell counts, total protein and ADA in PE were independent risk factors for MPE.Conclusions: PE is a complication of MM, and it is likely to be malignant. Low serum total protein and albumin levels are independent risk factors for MM with PE. Hypocomplement C3emia (activation of the complement bypass pathway) may affect the formation of PE in patients with MM. High nucleated cell counts, total protein and ADA levels as well as low LDH levels in PE were independent risk factors for MPE.