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Objectives: Recent studies suggest that intraindividual variability (IIV) of neuropsychological performance may be sensitive to HIV-associated neurologic compromise. IIV may be particularly dependent upon the integrity of frontal-subcortical systems, and therefore may be a meaningful phenotype in HIV. We examined the relationship between change in IIV and white matter integrity among HIV seropositive (HIV+) and HIV seronegative (HIV−) individuals. Method: The sample consisted of 38 HIV+ participants and 26 HIV− control participants who underwent neuroimaging and a neuropsychological evaluation at baseline and at 2-year follow-up evaluation. Results: Among HIV+ participants, increases in IIV (greater dispersion) were related to lower fractional anisotropy (FA) values in the anterior thalamic radiations (ATR) and the superior longitudinal fasciculus (SLF). Changes in mean-level global cognitive functioning were not significantly related to white matter integrity. Additionally, there was a significant Group × IIV interaction effect in the SLF demonstrating that the relationship between IIV and white matter integrity was specific to HIV. Conclusions: Overall, findings suggest that IIV may be more sensitive, relative to mean-level global cognitive functioning, in the detection of neurologic compromise among HIV+ individuals.