Loss of a whole chromosome 5 or a deletion of the long arm of chromosome 5, -5/del(5q), is a recurring abnormality in myeloid neoplasms. The APC gene is located at chromosome band 5q23, and is deleted in more than 95% of patients with a -5/del(5q), raising the question of whether haploinsufficiency of APC contributes to the development of myeloid neoplasms with loss of 5q. We show that conditional inactivation of a single allele of Apc in mice leads to the development of severe anemia with macrocytosis and monocytosis. Further characterization of the erythroid lineage revealed that erythropoiesis is blocked at the early stages of differentiation. The long-term hematopoietic stem cell (LT-HSC) and short-term HSC (ST-HSC) populations are expanded in Apc-heterozygous mice compared with the control littermates; however, the HSCs have a reduced capacity to regenerate hematopoiesis in vivo in the absence of a single allele of Apc. Apc heterozygous myeloid progenitor cells display an increased frequency of apoptosis, and decreased in vitro colony-forming capacity, recapitulating several characteristic features of myeloid neoplasms with a -5/del(5q). Our results indicate that haploinsufficiency of Apc impairs hematopoiesis, and raise the possibility that loss of function of APC contributes to the development of myelodysplasia.