West Nile virus (WNV) is an emerging mosquito-transmitted encephalitis virus first recognized in North America in 1999. The pathologic manifestations of WNV infection have not been well defined. This study documents the clinicopathologic features, including autopsy findings, of 2 cases: an 81-year-old man who contracted WNV infection with meningoencephalitis and a polio-like paralysis and a hospitalized 74-year-old woman with meningoencephalitis who acquired WNV through transfusion. The pathologic findings in both cases were marked by perivascular and leptomeningeal chronic inflammation, microglial nodules, and neuronophagia, predominantly involving the temporal lobes and brainstem. These findings also were present in the spinal cord, especially the lumbar region, of the patient with polio-like paralysis. In both cases, most of the inflammatory infiltrate was composed of CD3+ T lymphocytes (a predominance of CD8+ over CD4+ T cells), CD68+ macrophages, and rare CD20+ B lymphocytes. These cases further define the clinical and pathologic spectrum of central nervous system disease in WNV infection.