The postulated dual roles of survivin as an anti-apoptotic factor and a mitotic inducer have placed this factor in the spotlight of cancer research. The purpose of this study was to investigate whether survivin might connect the cell cycle with apoptosis. Here, by simultaneously monitoring survivin deficiency-induced morphological changes of HepG2 cells using time-lapse imaging as well as determining apoptosis progression, we observed synchronized defective mitosis characterized by multinucleated and polyploid cells and cell cycle arrest at S phase or G2/M phase followed by apoptosis, the processes of which depended on the simultaneous destruction of specialized subcellular compartments of survivin and activation of caspase-3-like protease. These findings showed that the survivin protein acted as mitotic regulator and apoptosis inhibitor, but may also possess the role of a bridge in integrating apoptosis and cell division. An essential prerequisite of this pathway was the specialized subcellular localization of survivin. The overexpression of survivin was required to maintain cell viability and proper cell cycle transitions, and to preserve genetic fidelity during cell division in HepG2 cells.