Myoblast transplantation is an experimental therapy that may be useful in hereditary muscle diseases. One obstacle to this approach is immune rejection. We evaluated human myoblasts and myotubes for surface expression of HLA class I and II histocompatibility antigens. The myoblast preparations, cultured from muscle biopsy specimens, were more than 95% pure as assessed by immunostaining with the Leu19 monoclonal antibody that reacts with human myoblasts and regenerating muscle fibers. Myoblasts and myotubes constitutively expressed HLA-class I but not HLA-class II molecules. However, HLA-class II expression was induced on mononucleated myoblasts after culture for 5 days in the presence of recombinant human interferon-gamma. The results indicate that transplanted myoblasts can be rejected because of histoincompatibility at the HLA-class I and HLA class II locus. Furthermore, an aberrant expression of HLA-class II antigen on myoblasts in vivo may play a role in the pathogenesis of autoimmune muscle disorders.