Recent studies showing that microglia internalize the amyloid β-peptide (Aβ) suggest that these cells have the potential for clearing Aβ deposits in Alzheimer's disease, and mechanisms that regulate the removal of Aβ may therefore be of clinical interest. Previous studies from this laboratory showing that C1q enhances phagocytosis of cellular targets by rat microglia prompted the current investigations characterizing the effects of C1q on microglial phagocytosis of Aβ. Microglia were shown to phagocytose Aβ1-42, in agreement with observations of other investigators. Uptake of Aβ1-42 was observed for concentrations of 5–50 μM, and phagocytosis of peptides containing ¹⁴C or fluorescein (FM) labels was not affected by the interaction of microglia with C1q-coated surfaces. However, inclusion of C1q (125 nM–1.4 μM) in solutions of 50 μM Aβ1-42 inhibited the uptake of ¹⁴C-Aβ1-42 and FM-Aβ1-42, suggesting that C1q blocks the interaction of Aβ with microglia. Uptake of Aβ was partially blocked by the scavenger receptor ligands polyinosinic acid and maleylated BSA. Inhibition of Aβ uptake by C1q may contribute to the accumulation of fibrillar, C1q-containing plaques that occurs in parallel with disease progression. These data suggest that mechanisms which interfere with the binding of C1q to Aβ may be of therapeutic value both through inhibition of the inflammatory events resulting from complement activation and via altered access of Aβ sites necessary for ingestion by microglia.