Microglial phagocytosis contributes to the maintenance of brain homeostasis. Mechanisms involved however, remain unclear. Using Aβ 42 solely as a stimulant, we provide novel insight into regulation of microglial phagocytosis by rafts. We demonstrate the existence of an Aβ 42 threshold level of 250pg/ml, above which microglial phagocytic function is impaired. Low levels of Aβ 42 facilitate fluorescent bead uptake, whereas phagocytosis is inhibited when Aβ 42 accumulates. We also show that region-specific raft clustering occurs prior to microglial phagocytosis. Low Aβ 42 levels stimulated this type of raft aggregation, but high Aβ 42 levels inhibited it. Additionally, treatment with high Aβ 42 concentrations caused a redistribution of the raft structural protein flotillin1 from low to higher density fractions along a sucrose gradient. This suggests a loss of raft structural integrity.Certain non-steroidal anti-inflammatory drugs, e.g. the COX-2-specific NSAID, celecoxib, raise Aβ 42 levels. We demonstrated that prolonged celecoxib exposure can disrupt rafts in a manner similar to that seen in an elevated Aβ 42 environment: abnormal raft aggregation and Flot1 distribution. This resulted in aberrant receptor recruitment to rafts and impaired receptor-mediated phagocytosis by microglial cells. Specifically, recruitment of the scavenger receptor CD36 to rafts during active phagocytosis was affected. Thus, we propose that maintaining raft integrity is crucial to determining microglial phagocytic outcomes and disease progression.