We describe a girl, one of monozygotic (MZ) twins, with endocrine dysfunction with precocious puberty, café-au-lait nevi and polyostotic fibrous dysplasia (PFD), McCune-Albright syndrome (MAS). After treatment with cyproterone acetate for 7 years the precocious puberty and excess growth improved but the bone-age still remain advanced. The co-twin had an advanced bone-age and a small café-au-lait spot, but showed neither endocrinopathy nor fibrous dysplasia of bone. On the basis of the findings in these twins, together with those in previously reported familial cases of MAS, including two pairs of MZ twins, a 2-hit mutation hypothesis is proposed: a dominant mutation may be inherited and leads to PFD in offspring as the primary defect of MAS; the second mutation may occur in somatic cell leading to mosaicism and thus resulting in MAS. This concept explains not only sporadic cases of MAS but also reported familial cases. If we assume that the second mutation occurred in an early somatic division, it would explain the discrepancy of clinical manifestation between MZ twins.