Red blood cells are essential for the survival of aerobic organisms. Mutations in proteins composing the RBC plasma membrane give rise to a spectrum of diseases characterized by hemolysis, inefficient gas exchange, and anemia. Here, we test whether nuclear envelope (NE) protein, emerin (EMD), is also expressed in a nuclear cell types to regulate membrane structure and function. We find that emerin is indeed localized to the RBC plasma membrane and regulates the localization of other membrane proteins involved in actin branching and cytoskeletal dynamics. Additionally, we find that loss of Emd (X chromosome gene) expression results in decreased corpuscular volume (MCV) and hemoglobin content with a sex-specific increase in RBC number and hematocrit, consistent with other male-dominated EMD phenotypes. After FACS sorting of erythroid progenitor species from  bone marrow, we found that only male Emd KO mice had decreased proerythoblasts, suggesting an increased rate of erythroid differentiation in these animals. The conserved decrease in circulating cell MCV also correlated with a protective effect from osmotic hemolysis. We found that human EMD mutations also correlated with increased hematocrit and RBC numbers with a mild but significant effect on MCV and MCH. Individuals with emerin-dependent Emery-Dreifuss muscular dystrophy (EDMD) also demonstrate a mild yet consistent RBC phenotype according to patient CBC data. While these results identify a novel role for emerin, more data is required to fully understand the mechanisms by which emerin regulates erythropoiesis in the bone marrow and membrane shape and size in mature erythrocytes. With the support of the YCCEH in completing the included proposed aims with super resolution microscopy and hematopoietic progenitor FACS, we are confident that we will identify a novel EMD-dependent mechanism regulating erythroid differentiation and structural integrity that will be a significant contribution to the fields of membrane biology, EDMD disease pathology, and sex as a biological variable in hematology.