Rett syndrome (RTT) is an autistic spectrum disorder with a known genetic basis. RTT is caused by loss of function mutations in the X-linked gene MECP2 and is characterized by loss of acquired motor, social and language skills in females beginning at 6–18 months of age. MECP2 mutations also cause non-syndromic mental retardation in males and females, and abnormalities of MeCP2 expression in the brain have been found in autistic spectrum disorders. We studied home-cage behavior and social interactions in a mouse model of RTT (Mecp2^308/Y) carrying a mutation similar to common RTT causing alleles. Young adult mutant mice showed abnormal home-cage diurnal activity in the absence of motor skill deficits. Nesting, a phenotype related to social behavior, and social interactions were both impaired in these animals. Mecp2^308/Y mice showed deficits in nest building and decreased nest use. Although there were no differences in aggression or exploration of novel inanimate stimuli, mutant mice took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. The abnormalities of diurnal activity and social behavior in Mecp2^308/Y mice are reminiscent of the sleep/wake dysfunction and autistic features of RTT. These data suggest that MECP2 regulates the expression and/or function of genes involved in social behavior. The study of Mecp2^308/Y mice will allow the identification of the molecular basis of social impairment in RTT and related autistic spectrum disorders.