Infection with a particularly neurovirulent strain of HIV has been hypothesized to explain why only a subset of patients develops HIV encephalitis. We studied the third hypervariable region (V3) of multiple clones from both brains and spleens of three patients who died with HIV encephalitis, to see if there was a molecular signature associated with neurological disease. Clones from the spleen and brain of individual patients showed significant nucleic acid homology and had envelope sequences characteristic of macrophage-tropic viruses. No brain-specific unique sequences were observed, suggesting that while CNS virus is macrophage tropic there is no evidence in the V3 envelope region studied to suggest a specific neurotropic variant.