Mental retardation is the most common developmental disability affecting 2-3% of the population, a consequence of a wide range of genetic or nongenetic etiologic factors. The cause of mental retardation remains unknown in about 50% of cases. Trp53 (transformation related protein 53, also known as p53) is a tumor suppressor gene that activates the expression of genes involved in inducing growth arrest of cells in response to multiple forms of cellular stress and it plays a significant role in apoptotic cell death during the early development of the nervous system. In this study, we examined 246 children with nonsyndromic mental retardation from three Italian populations and 213 healthy children from the same populations. We observed that the Pro72/Pro72 genotype of p53 is much less represented in children with nonsyndromic mental retardation than in controls (6.5% versus 14.08%) (OR=0.42; 95% CI 0.21-0.83). These data suggest that subjects carrying the Pro allele are protected from this disease.