Objective: To study the clinical manifestations, cytopathological diagnosis and differential diagnosis of the malignant melanoma with serosal effusion. Methods: Five cases of malignant melanoma diagnosed by the cytology of serosal effusion in XijingHospital were enrolled. The cytology of serosal smear and the immunocytochemical staining of the paraffin-embedded section prepared from centrifugation of the serous effusion were studied, and the clinical feature and prognosis of the patients were analyzed. Results: Five cases included 2 males and 3 females, the age of onset ranged from 30 to 71 years and the average age was 48.6 years. Three cases had pleural effusion and 2 cases had intraperitoneal effusion. Five cases were diagnosed as malignant melanoma by morphological observation in the serosal smear and immunocytochemistry examination(all case was positive for HMB45, S-100, Pan-mel, SOX10 and vimentin). All patients were followed up until April 2020, with a follow-up period of 2 to 11 months. In 5 cases, three died, one survived and one was lost during follow-up. Conclusions: The serous cavity effusion caused by malignant melanoma is very rare, and the diagnosis is not difficult since most cases have clear history. The malignant melanoma diagnosed by the cytology of serosal effusion need to be differentiated with the poorly differentiated adenocarcinoma, lymphoma, and malignant mesothelioma. Centrifugation of the serosal effusion and immunocytochemical staining is helpful to make diagnosis. It is important to confirm the diagnosis by performing cytological examination of serous effusion accurately and timely because of the low survival rate of metastatic malignant melanoma.