Objective: To evaluate whether the amyloid-binding agent carbon 11-labeled Pittsburgh Compound B ( 11C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants. Design: 11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both χ 2 and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer's Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-βprotein 1-42 (Aβ42) using 11C-PiB. Setting: An ADRC and HIV clinic. Participants: Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD). Main Outcome Measures: Mean and regional 11C-PiB binding potentials. Results: Participants with symptomatic AD were older (P<.001), had lower CSF Aβ42 levels (P<.001), and had higher CSF tau levels (P<.001) than other groups. Regardless of degree of impairment, HIV-positive participants did not have increased 11C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P<.001). Conclusions: Middle-aged HIV-positive participants, even with HAND, do not exhibit increased 11C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross-sectional and longitudinal studies are required to assess the utility of 11C-PiB in older individuals with HAND.