Acute liver damage is considered to be the major cause of mortality after massive hepatectomy. Prostaglandin E1 (PGE1) and somatostatin (SST) have been shown to protect against hepatic injury of rats after partial hepatectomy. However, the precise mechanisms remain largely unknown. In this study, we examined the effects of PGE1, SST and the combination of these two drugs on acute liver damage of rats after 90% hepatectomy. We found that animal survival was improved when pretreated with PGE1 and SST. Portal venous pressure (PVP), serum alanine aminotransferase (ALT) and aspartate aminotransaminase (AST), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were all reduced after administration of PGE1 and SST. In addition, apoptosis was inhibited via upregulation of Bcl-2 and downregulation of Bax and caspase-3 in drug treatment groups. Furthermore, pretreatment with PGE1 and SST alleviated endoplasmic reticulum (ER) stress by induction of heat shock protein 70 (HSP70) and glucose-regulated protein 78 (GRP78), but suppression of transcription factor C/EBP homologous protein (CHOP). Our data suggest that administration of PGE1 and SST, particularly in combination, may prevent acute liver damage of rats after massive hepatectomy by inhibiting inflammatory responses, apoptosis and ER stress.