Background: Duchenne muscular dystrophy is a progressive, lethal muscle-wasting disease for which there is no treatment. Materials & methods: We have isolated wild-type mesoangioblasts from aorta and tested their effectiveness in alleviating severe muscle disease in the dystrophin/utrophin knockout (mdx/utrn^-/-) mouse model for Duchenne muscular dystrophy. Results: Mesoangioblast clones express Sca-1 and Flk-1 and differentiate into smooth and skeletal muscle, glial cells and adipocytes in vitro. Mesoangioblasts proliferate in vivo, incorporate into muscle fibers, form new fibers, and promote synthesis of dystrophin and utrophin. Muscle fibers that have incorporated mesoangioblasts, as well as surrounding fibers, are protected from damage, with approximately 50-fold less damage than fibers in muscle injected with saline. Some mesoangioblasts localize beneath the basal lamina and express c-met, whereas others differentiate into smooth muscle cells at the periphery of vessels and express α-smooth muscle actin. In mdx/utrn^-/- muscle, some mesoangioblasts also form Schwann cells. Discussion & conclusion: Mesoangioblasts differentiate into multiple cell types damaged during the progression of severe muscle disease and protect fibers from damage. As such, they are good candidates for therapy of Duchenne muscular dystrophy and perhaps other neuromuscular diseases.