Proteus syndrome is a rare, complex disorder predominantly characterized by asymmetric overgrowth of body parts, connective tissue and epidermal nevi, and vascular malformations. General diagnostic criteria comprise mosaic distribution, sporadic occurrence, and progressive course. We report on Proteus syndrome in discordant monozygotic twins. The affected 9-year-old boy showed progressive postnatal overgrowth of his right leg and foot and asymmetric progressive overgrowth of single toes with a small cerebriform connective tissue nevus on his right fourth toe. The progressive course was documented by serial photographs over a period of 3 years. Twin monozygosity was determined by PCR-amplified short tandem repeat (STR) analysis, revealing complete concordance of all alleles in both twins. This observation, to our knowledge, is only the second case report of discordant Proteus syndrome in monozygotic twins. This supports the hypothesis that this rare condition is caused by a postzygotic mutational event resulting in mosaicism. © 2008 Wiley-Liss, Inc.