An adolescent with HIV/AIDS presented subacutely with progressive encephalopathy, spastic quadraplegia, and diarrhea. His brain biopsy was suggestive of central nervous system Whipple's disease, a disease rarely described in HIV patients. Due to overlapping, nonspecific symptoms associated with several opportunistic infections and to the difficulty in culturing the causative organism Tropheryma whipplei, Whipple's disease may be more common than previously suspected, and it is an important consideration in patients with AIDS.