Individuals with Williams syndrome (WS) show a specific deficit in visuo-spatial abilities. This finding, however, derives mainly from performance on small-scale laboratory-based tasks. This study investigated large-scale route learning in individuals with WS and two matched control groups (moderate learning difficulty group [MLD], typically developing group [TD]). In a non-labelling and a labelling (verbal information provided along the route) condition, participants were guided along one of two unfamiliar 1-km routes with 20 junctions, and then retraced the route themselves (two trials). The WS participants performed less well than the other groups, but given verbal information and repeated experience they learnt nearly all of the turns along the route. The extent of improvement in route knowledge (correct turns) in WS was comparable to that of the control groups. Relational knowledge (correctly identifying spatial relationships between landmarks), compared with the TD group, remained poor for both the WS and the MLD group. Assessment of the relationship between performance on the large-scale route-learning task and that on three small-scale tasks (maze learning, perspective taking, map use) showed no relationship for the TD controls, and only a few non-specific associations in the MLD and WS groups.