Oculopharyngeal muscular dystrophy (OPMD) is a late-onset polyalanine disorder characterized clinically by progressive ptosis, dysphagia, and limb weakness and pathological hallmarked by unique intranuclear inclusions in the muscles. It is caused by heterozygous expansion of a 10-alanine stretch to 12-17 alanine residues in the N-terminus of the poly(A)-binding protein, nuclear 1 (PABPN1). Although PABPN1 is a major component of the inclusions in OPMD, the associated pathogenic mechanism is undetermined. No animal models of OPMD have been discovered in nature; therefore, we generated transgenic mice expressing human PABPN1 (hPABPN1) using a chicken beta-actin (CAG) promoter. While transgenic mice lines expressing normal hPABPN1 did not show myopathic changes, lines expressing high levels of expanded hPABPN1 with a 13-alanine stretch showed myopathy phenotype with aging. The latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 and scattered rimmed vacuoles restricted in the muscles. In particular, the nuclear inclusions closely resembled those of OPMD muscles on electron microscopy, and myopathic changes were more prominent in the eyelid and pharyngeal muscles. The results demonstrated that we had established the first transgenic OPMD model mouse. Recently, two other transgenic mice expressing mutated hPABPN1 with a 17-alanine stretch have been generated; however, the transgenic mouse using its natural promoter did not show myopathy phenotype, and the other using the human skeletal actin (HSA1) promoter disclosed quite different intranuclear inclusions from those of human OPMD muscles. Our transgenic OPMD model mouse appears to have more dramatic alterations in myofiber viability, but is useful for elucidating of molecular mechanisms and establishing therapeutic trials.