Objectives: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-β42 (Aβ42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent C-Pittsburgh compound B (C-PiB), a biomarker for Aβ42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20). Methods: In this case-control study, all participants had an C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by χ tests. Participants were further divided into either low (<500 pg/mL) or normal (≥500 pg/mL) CSF Aβ42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Aβ42. Results: Regardless of CSF Aβ42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Aβ42 (<500 pg/mL) had high C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions. Conclusions: Cognitively unimpaired HIV+ participants, even with low CSF Aβ42 (<500 pg/mL), do not have C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Aβ42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Aβ42 and normal C-PiB are required.