The pre-lytic release mechanism of foot-and-mouth disease virus was investigated by immunofluorescence, acridine orange staining, and electron microscopy in infected bovine and porcine kidney coverslip cultures. Cells with cytoplasmic fluorescence and which were positive for single stranded RNA with acridine orange staining were observed at 2 h after infection. Scanning electron microscopy showed cytoplasmic blebs in all cultures examined 2 h after infection. Rounded cells with virus inclusions began to appear 3 h after infection. Rounded cells and cytoplasmic blebs were shown to have single stranded RNA by acridine orange staining. Immunofluorescence and transmission electron microscopy with immunoferritin tagging demonstrated foot-and-mouth disease virus in cytoplasmic blebs. This study presents evidence for a pre-lytic release of foot-and-mouth disease virus through virus-containing cytoplasmic blebs emerging from infected cells.