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To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure.Prospective cohort study of Thai participants in the earliest stages of HIV-1 infection.Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change.Participants were 31 ± 8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (p < 0.001) and caudate (p = 0.006). TBM confirmed significant atrophy in the putamen and caudate, as well as in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, p = 0.017), while the baseline density of PSGL-1-expressing inflammatory (CD14+CD16+) monocytes correlated with putamen atrophy (ρ = 0.65, p = 0.022).Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations.