Chronic infection with HIV is associated with neuroinflammation. Prior diffusion tensor imaging (DTI) studies demonstrated increased mean diffusion (MD) and decreased fractional anisotropy (FA) in the white matter (WM) and subcortical brain regions of HIV patients. The current study aims to detect whether there are greater than age-related brain changes in HIV patients after a 1-year follow-up period using DTI. Thirty-nine antiretroviral-stable HIV subjects and 32 HIV-seronegative (SN) controls were evaluated, with neuropsychological tests and DTI, at baseline and after 1 year. MD and FA in the genu and splenium of the corpus callosum and in six other subcortical and white matter regions were evaluated bilaterally. Compared to SN controls, HIV subjects had significantly higher MD in the frontal WM (p = 0.0104) and lower FA in the parietal WM (p = 0.006). After 1 year, HIV subjects showed increase in MD in frontal and parietal WM, putamen, and genu; HIV subjects also showed greater increased genu diffusion than SN controls (p = 0.005). Changes in global cognitive deficit score correlated with changes in MD in the genu and FA in the parietal and frontal WM and putamen (multiple regression, p = 0.0008). Lastly, normal age-dependent changes in frontal WM diffusion and FA in genu and putamen were not observed in HIV subjects. Since increased MD may reflect increased neuroinflammation, our findings suggest greater than normal age-related inflammatory changes in the genu of these HIV patients, which may contribute to the cognitive deficits. Measurements of MD in the genu may be useful for monitoring disease progression in HIV brain infection.