S-100 beta, a gene triplicated in Down Syndrome (DS), is thought to play a role in development of the brain in general, and in the serotonergic neuronal system in particular. We have been studying an animal model of DS, based on overexpression of this gene. In the current study, we report on the social behaviors of these animals, both in same-strain and mixed-strain pairings. In addition, as the neuropeptide oxytocin is often thought to be involved in social behaviors, we have looked at oxytocin-containing cells. In non-social behaviors, such as grooming and line-crossing, the S-100 beta animals were more active than the CD-1 control animals and showed significantly less social sniffing. In mixed-strain studies, these differences became more pronounced, with the CD-1 animals showing significantly greater levels of sniffing and anogenital sniffing. As well, the CD-1 animals showed more rearing and an increase in line crossings, suggesting a heightened level of vigilance or awareness of novelty. The S-100 beta animals, conversely, did not appear to respond to the novelty of the CD-1 animals. In mixed pair studies, the S-100 beta animals more frequently took submissive postures, while the CD-1 animals more frequently took dominant postures, and showed a significant increase in biting the S-100 beta partner. The S-100 beta animals showed less rearing, perhaps a further indication that they were inhibited by the CD-1 animals. Analysis of oxytocin-containing neurons showed comparable levels in the supraoptic and paraventricular nuclei of the hypothalamus, but significantly reduced numbers of cells in the bed nucleus of the stria terminalis of the S-100 beta animals. These results are discussed in terms of oxytocin contributions to socialization and fear responding and the significance of these findings to DS.