Expression of the Kaposi's sarcoma-associated herpesvirus (KSHV) cyclin D homolog, K cyclin, is thought to contribute to viral oncogenesis. We show that K cyclin expression in primary cells sensitizes to apoptosis and induces growth arrest, both of which are dependent on p53 but independent of E2F1 or p19(ARF). DNA synthesis, but not cytokinesis, continues in K cyclin-expressing cells, leading to multinucleation and polyploidy. Such polyploid cells exhibit pronounced centrosome amplification and consequent aneuploidy. Our data suggest that K cyclin expression leads to cytokinesis defects and polyploidy, which activates p53. However, in the absence of p53, such cells survive and expand as an aneuploid population. Corroborating these findings, in vivo Emu; K cyclin expression cooperates with p53 loss in the induction of lymphomas.