Objective: Increased intra-individual variability (IIV) on neuropsychological testing may be a harbinger of incipient functional decline, though considerable variability is present in healthy individuals as well. To investigate the prognostic relevance of IIV, the current study examined the relationship between increasing IIV on neuropsychological testing and declines in medication adherence among a cohort of HIV-infected adults. Method: One hundred and fifty HIV-seropositive (HIV+) participants underwent neuropsychological assessment at baseline and 6 months later. Medication adherence rates were tracked using MEMS caps over the 6-month study. Dispersion was calculated as the within-subject standard deviation of neuropsychological T-scores. Mean and dispersion ratio change scores were calculated as the difference of values between the two time points divided by the baseline value. Results: After controlling for drug use and depression, the overall model was significant, adjusted R2 = .15, p < .01. The dispersion ratio variable emerged as a significant predictor, (β = −.27, p < .01) while the mean ratio variable was not significant. The sample was split into high and low IIV groups. Post-hoc tests indicated that the memory and motor domains exhibited more variability in the high IIV group. Conclusion(s): Results support that increased IIV is an early signal of functional decline that is above and beyond changes in global mean neurocognition. Increased IIV appears to be driven by neurocognitive domains known to be adversely affected by HIV, with relative sparing in other domains. Changes in IIV may be important to evaluate for when there is a suspicion of compromised neurological functioning in HIV.