The vast majority of malignant pleural effusions are caused by metastatic adenocarcinoma, most frequently from breast or lung primaries. However, a minority of cases show evidence of involvement by a hematopoietic neoplasm such as lymphoma or leukemia. We report a rare case of a 54-year-old male with a prior diagnosis of acute myeloid leukemia with myelodysplastic-related changes (AML-MDS) with erythroid differentiation having new onset pleural effusions containing leukemic blasts. The pleural specimen was comprised of blast forms having large round nuclei with finely dispersed chromatin and prominent nucleoli, with scattered binucleate forms. The blasts expressed CD45 and CD34 and were negative for epithelial and mesothelial markers. Previous bone marrow biopsies had shown that the blasts exhibited strong staining for hemoglobin and lacked expression of Factor VIII and myeloperoxidase, consistent with erythroid differentiation. Although rare, this case indicates the need for consideration of unusual disease states presenting within a pleural fluid and highlights the differential diagnosis and immunohistochemical profile of AMLs with erythroid differentiation.