Enhanced endoplasmic reticulum (ER) stress has been implicated in various pathological situations including inflammation. During a search for compounds that regulate ER stress, we identified vaticanol B, a tetramer of resveratrol, as an agent that protects against ER stress-induced cell death. Vaticanol B suppressed the induction of the unfolded protein response (UPR)-targeted genes such as glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP), after treating the cells with ER stressors. Analysis in a mouse macrophage cell line RAW 264.7 revealed that vaticanol B also possesses a strong anti-inflammatory activity. Production of a variety of inflammatory modulators such as TNF-,nitric oxide (NO), and prostaglandin E2 was inhibited by vaticanol B to a much greater extent than it was by monomeric or dimeric resveratrol after exposing the cells to lipopolysaccaride (LPS). Further investigations to determine the common mechanisms underlying the regulation of ER stress and inflammation by vaticanol B disclosed an important role for vaticanol B in the regulation of basic gene expression and in the prevention of the protein leakage from the ER into the cytosol in both conditions. These results suggest that vaticanol B is a novel anti-inflammatory agent which improves the ER environment by reducing the protein load on the ER and by maintaining the membrane integrity of the ER.