This study aimed to compare serum amyloid processing biomarkers among HIV subtype B (n = 25), HIV subtype C (n = 26), healthy HIV-negative controls (n = 18), and patients with Alzheimer's disease (AD; n = 24). Immunoassays were used to measure main soluble Aβ isoforms Aβ38, Aβ40, Aβ42, and Aβ-total in serum and cerebrospinal fluid (CSF). People living with HIV (PLWH) and HIV(-) samples, including AD samples, were compared for gender and age, while HIV subtypes were compared for nadir CD4 and plasma viral load suppression. CSF/serum ratios of Aβ40, Aβ42, and Aβ-total were lower in HIV-1C group than in HIV-1B group (p = 0.020, 0.025, and 0.050, respectively). In serum, these biomarkers were comparable. Serum Aβ isoforms were significantly lower in PLWH than in AD. Serum Aβ42 levels in PLWH were decreased compared to those in control group, thus similar to Aβ42 alterations in CSF; these results were different from those observed in AD. Impaired cellular immunity, low CD4 cell count (nadir or current) influences serum Aβ metabolism in HIV-1B but not HIV-1C. However, in PLWH overall, but not in individual HIV subtype groups, greater CD4 recovery, calculated as the difference between current and nadir CD4, correlated with Aβ42/Aβ40 ratio in serum (rs 0.246; p = 0.0479). No significant correlation was found with global deficit score (GDS), an index of neurocognitive performance, age, or duration of infection. These findings are consistent with those of subtype-dependent amyloid processing in blood in chronic HIV disease.