Hantaviruses are maintained in nature in persistently infected rodents and can also persistently infect cultured mammalian cells, causing little or no cytopathology. An unexpected outcome of this study was the observation of cytopathic effects (CPE) in the hantavirus-infected human embryonic kidney cell line HEK293. It was confirmed that hantaviruses induce apoptosis in HEK293 cells, although apoptosis appeared mostly in uninfected, bystander cells and rarely in infected HEK293 cells. Although studies by others suggest that the nucleocapsid protein of Puumala virus interacts with the Fas-mediated apoptosis enhancer Daxx at the gene expression level, it was determined that members of the TNF receptor superfamily did not contribute to the apoptosis observed in infected HEK293 cells. The observation of CPE in HEK293 cells might lead to a better understanding of the mechanisms of persistence and pathogenesis in hantavirus infections.