Microcystin produced by cyanobacteria in diverse water systems is a potent hepatotoxin that has been documented to induce hepatocyte apoptosis and liver injury. There are more than eighty reported microcystins. The present work aimed at investigating the apoptotic effect of MC-RR (a common member of microcystin family), and its related mechanism. MC-RR was administered orally to ICR mice for 7 days with different dosages. Apoptotic cell death in liver was detected by TUNEL assay, and the expression levels of Bcl-2, Bax and p53, GRP 78 and CHOP which have been reported to be related to apoptosis and ER stress were determined via western-blot. The activity of PP2A was measured using the serine-threonine phosphatase assay system and PP2A A subunit expression at both transcription and protein levels was measured by RT-PCR and western blot, respectively. A significant difference was observed on the number of TUNEL positive liver cells between the control and MC-RR-treated groups. The expression levels of Bcl-2, Bax, p53, and GRP 78 in MC-RR-treated groups were altered significantly compared to the control, but no obvious alteration was found in CHOP expression. The PP2A activity and A subunit expression did not manifest any obvious change at both transcription and protein levels. The results indicated that oral exposure to MC-RR can cause apoptosis as well as moderate ER stress in mice liver. The mitochondrial pathway via Bcl-2 family members may contribute to the apoptosis. However, PP2A may not be involved in the regulation of apoptotic process under the current conditions. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2010.