Clinical, pathologic, and immunologic features of two patients with progressive multifocal leukoencephalopathy and multiple coexisting central nervous system infections are presented. Both showed impaired cell-mediated immunity whereas immunoglobulins were normal, suggesting that defective cellular rather than humoral immunity predisposes to progressive multifocal leukoencephalopathy. Continued neurologic deterioration might be due not only to progression of the condition but also to simultaneous opportunistic bacterial and fungal infections that may be amenable to treatment. Unusual features in case 1 included striking neurologic remission for 8 months and a positive brain scan corresponding to a large demyelinated lesion in the frontal lobe.