Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant disorder with a characteristic and distinctive distribution of weakness but a high degree of variation in the age of onset and rate of progression. Monozygotic twins provide the opportunity to assess the relative importance of genetic as opposed to nongenetic influences on the course of disease. We have studied three sets of monozygotic twins with FSHD and compared the similarity of their degree of involvement using quantitative studies of individual muscle function. Similar quantitative studies of 59 other subjects with FSHD served as a reference population for contrast with the twin studies. One set of twins was discordant for FSHD, presumably as a reflection of a postzygotic mutation in the affected twin. The other two sets were concordant and both had evidence of autosomal dominantly inherited gene rearrangements. Both sets were similarly affected in terms of age of onset, overall degree of disability, and quantitative tests of muscle, but there were major differences in the symmetry of involvement of specific muscles. Cerebral dominance was not related to asymmetries of involvement. These data suggest age of onset and severity are determined by the gene lesion in FSHD. Other factors may influence the frequently encountered asymmetries in FSHD.