SOD1 is one of several overexpressed genes in trisomy 21. In order to dissect possible genetic causes of the syndrome, wild-type SOD1/SOD1 transgenic mice were compared to FVB/N non-transgenic controls at 5 months of age in tests of exploratory activity and motor coordination. Wild-type SOD1/SOD1 transgenic mice had fewer stereotyped movements in an open-field and fell sooner from a rotorod than controls. In contrast, wild-type SOD1/SOD1 transgenic mice had fewer falls on a wire suspension test. There was no intergroup difference for ambulatory movements in the open-field, exploration of the elevated plus-maze, emergence from a small compartment, and motor coordination on a stationary beam. These results indicate that homozygous mice expressing human SOD1 are impaired in their ability to adjust their posture in response to a moving surface and make fewer small-amplitude movements without any change in general exploratory activity.