Cytologic preparations from two cases of progressive multifocal leukoencephalopathy (PML) were obtained by stereotactically guided needle biopsies using computerized tomograms of the brain. Case 1 was a 32-year-old man with an acquired immunodeficiency syndrome-related complex. Case 2 was a 71-year-old man with chronic lymphocytic leukemia. Smears showed moderate cellularity, consisting of moderately to markedly atypical cells with enlarged hyperchromatic nuclei. The chromatin pattern showed smudging, with or without clumping, similar in pattern to the human polyomavirus-infected "decoy" cells seen in urine cytology. Nuclei were predominantly round to oval, smoothly contoured and often stripped of cytoplasm. Occasional bizarre lobulated or multinucleated forms were seen. Some atypical cells had abundant cytoplasm exhibiting stellate projections. Histologic sections of the biopsy material confirmed the diagnosis in each case. In both cases, electron microscopy demonstrated intranuclear polyoma-type virus particles. The present findings suggest that PML should be considered in the differential diagnosis of marked cytologic atypia in brain aspirates from immunocompromised patients.