Activated microglia, overexpressing the potent neuroactive cytokine interleukin-1, have been implicated as a driving force in the evolution of diffuse amyloid deposits into diagnostic neuritic plaques in Alzheimer's disease. To evaluate this role further, we used double-label immunohistochemistry to classify and quantify plaque-associated and non-plaque-associated activated interleukin-1-immunoreactive microglia in parahippocampal tissue from 11 patients with Alzheimer's disease. These activated microglia were subclassified as primed (only slightly enlarged), enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents). We further determined the distribution of these microglial subtypes among four defined plaque types. Most (84%) primed microglia were not plaque associated, although 13% were present in diffuse non-neuritic plaques and 3% were present in diffuse neuritic plaques. In contrast, most enlarged (55%) and phagocytic (91%) microglia were plaque associated. Of plaque-associated enlarged microglia, most (71%) were found in diffuse neuritic plaques with the remainder evenly distributed between diffuse non-neuritic and dense-core neuritic plaques (15% each). Of plaque-associated phagocytic microglia, a few were present in diffuse non-neuritic plaques (5%), but most were found in diffuse neuritic plaques (62%) and dense-core neuritic plaques (33%). These findings show preferential association of primed microglia with diffuse amyloid deposits and imply that microglial transformation from primed, to enlarged, to phagocytic types occurs in concert with the evolution of amyloid plaques from diffuse amyloid deposits to the neuritic beta-amyloid plaque forms in Alzheimer's disease. Microglial phagocytic activity in neuritic plaques may reflect involvement in the processing of diffuse amyloid into condensed beta-amyloid, or in clearance of neuritic debris.