Background: Prior studies have shown that cyclooxygenase 2 (COX-2), an enzyme involved in inflammatory mechanisms and neuronal activities, is up-regulated in the brain with Alzheimer disease (AD) and may represent a therapeutic target for anti-inflammatory treatments. Objective: To explore COX-2 expression in the brain as a function of clinical progression of early AD. Design and Main Outcome Measure: Using semi-quantitative immunocytochemistry, we analyzed COX-2 protein content in the hippocampal formation in 54 postmortem brain specimens from patients with normal or impaired cognitive status. Setting and Patients: Postmortem study of nursing home residents. Results: The immunointensity of COX-2 signal in the CA3 and CA2 but not CA1 subdivisions of the pyramidal layers of the hippocampal formation of the AD brain increased as the disease progressed from questionable to mild clinical dementia as assessed by Clinical Dementia Rating. COX-2 signal was increased in all 3 regions examined among cases characterized by severe dementia. Conclusion: Neuronal COX-2 content in subsets of hippocampal pyramidal neurons may be an indicator of progression of dementia in early AD.