Youths with perinatally infected HIV survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. Since changes in cognitive function may be preceded by subtle changes in brain function, resting-state functional magnetic resonance imaging (rs-fMRI) may become useful in evaluating functional connectivity in these youths. We evaluated alterations in brain functional connectivity in eight perinatally HIV-infected youths and eleven healthy controls. Results from this study demonstrate that, compared to normal subjects, the strength of the several networks connectivity including DMN, Dorsal Attention, Lateral Visual, were significantly decreased in several regions among perinatally HIV-infected youth. The detailed mechanisms, implications of these brain activities and networks exhibiting changes will require further investigation.