Introduction: MTA Plus is a new calcium silicate cement with unknown cytotoxicity characteristics. The objectives of this study were to examine the effect of MTA Plus on the viability, apoptosis/necrosis profile, and oxidative stress levels of rat odontoblast-like cells. Methods: MDPC-23 cells were exposed to gray and white MTA Plus (GMTAP, WMTAP), gray and white Pro- Root MTA (GMTA, WMTA) cements, or their eluents. The cells were evaluated for (1) cell viability by using XTT assay, (2) apoptosis/necrosis by using flow cytometry and confocal laser scanning microscopy, and (3) oxidative stress by measuring reactive oxygen species. Results: XTT assay showed that all test cements exhibited marked initial cytotoxicity that decreased with time. By the end of the third week, GMTAP and GMTA were comparable to untreated cells (negative control) in terms of cell viability, whereas WMTAP and WMTA were significantly lower than the untreated cells. Apoptosis/necrosis profiles of cells exposed to WMTAP and GMTAP were not significantly different from untreated cells, whereas cells exposed to WMTA and GMTA showed significantly less viable cells. All experimental groups exhibited reduction of intracellular reactive oxygen species formation compared with untreated cells, although cells exposed to WMTA were not significantly different from untreated cells. Conclusions: Both the gray and white versions of MTA Plus possess negligible in vitro cytotoxic risks that are time and dilution dependent. They enrich the spectrum of hydraulic calcium silicate cements currently available to clinicians for endodontic applications. (J Endod 2014;40:255–260)