The SWI2/SNF2 family ATPase, p400/mDomino, is a core subunit of a large chromatin-remodeling complex, and is currently suggested to play a unique function in histone variant exchange, a process by which chromatin structure is altered. Here, we investigated the role of p400/mDomino in mammalian development by generating mutant mice with a targeted deletion of the N-terminal domain of p400/mDomino (referred to as mDom(DeltaN/DeltaN)). The mDom(DeltaN/DeltaN) mice died on embryonic day 11.5 (E11.5), and displayed an anemic appearance and slight deformity of the neural tube. DNA microarray and quantitative RT-PCR analyses revealed that all of the embryonic globin genes and a globin chaperone gene were poorly expressed in the mDom(DeltaN/DeltaN) embryo and yolk sac on E8.5, indicating that primitive erythropoiesis was impaired. A hematopoietic colony assay indicated that the hematopoietic activity of the yolk sac was significantly blocked in the mutant mice. We also found that the expression of a limited set of Hox genes, including Hoxa7, Hoxa9 and Hoxb9, was drastically enhanced in the mDom(DeltaN/DeltaN) yolk sacs. These results suggest that p400/mDomino plays a critical role in embryonic hematopoiesis by regulating the expression of developmentally essential genes such as those in the Hox gene cluster.