There is cross-sectional evidence that neurocognitive intra-individual variability (IIV), or dispersion, is elevated in human immunodeficiency virus (HIV) disease and is associated with declines in activities of daily living, including medication adherence. This longitudinal study extends this literature by examining whether increased neurocognitive IIV in HIV-positive persons over time predicts declines in medication adherence above and beyond changes in mean level of performance over a 6-month observation. After controlling for drug use, declines in mean performance, and changes in depressive symptoms, results confirmed that increases in IIV were associated with overall poorer antiretroviral medication adherence. HIV-positive individuals with the greatest increases in dispersion demonstrated marked reductions in adherence by the third month that exceeded what was observed in less variable individuals. Our results indicate that increases in dispersion are associated with poorer declines in medication adherence in HIV disease, which may have implications for the early detection and remediation of suboptimal antiretroviral adherence.