Mental rotation, the ability to manipulate three-dimensional objects in space, is a widely studied and neurally complex aspect of spatial cognition that has been largely ignored in the HIV literature. The authors report evidence of a significant interaction between HIV serostatus and performance on mental rotation tasks, whereby individuals with HIV (n=19) committed a greater number of errors than demographically similar seronegative persons (n=15) on Luria's hand rotation task (d=0.74, p<0.05), but not on the corresponding parallelogram rotation task (p>0.10). Hand rotation errors were associated with worse performance on measures of executive functions and working memory, but not with measures of visuoperception. Considered in the context of the preferential frontostriatal neuropathology of HIV-associated neurocognitive disorders, these preliminary findings suggest that the observed deficit in the mental rotation of hands may arise from a disrupted fronto-striato-parietal network.