We describe 4 patients identified over 5 years with large atypical cells on the feathered edge of routinely prepared peripheral blood films. Films were reviewed either as part of a blood film consultation or a bone marrow examination. The cells were 50 to 60 microns in diameter, with granular eosinophilic cytoplasmic inclusions and eccentric enlarged nuclei. Additional studies including buffy coat preparations and immunohistochemistry revealed that these were circulating cytomegalovirus (CMV)-infected cells, most likely of endothelial origin. All patients were immunocompromised (3 had HIV infection, and 1 was an organ transplant recipient) and had clinical evidence of CMV infection. The unique appearance of these cells at Wright-Giemsa staining, and their possible misidentification as malignant cells or other cells, highlights the need for pathologists to be aware of their morphologic features and possible clinical implication.