The hallmark of familial amyloid polyneuropathy (FAP) is the presence of extracellular deposits of transthyretin (TTR) aggregates and amyloid fibers in several tissues, particularly in the peripheral nervous system. The molecular pathways to neurodegeneration in FAP still remain elusive; activation of nuclear factor kappaB, pro-inflammatory cytokines, oxidative stress, and pro-apoptotic caspase-3 has been demonstrated "in vivo" in clinical samples and in cell culture systems. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress response in FAP by showing activation of the classical unfolded protein response pathways in tissues not specialized in TTR synthesis but presenting extracellular TTR aggregate and fibril deposition. We also proved cytotoxicity by Ca2+ efflux from the ER in cell cultures incubated with TTR oligomers. Taken together, these studies evidence ER stress associated with a extracellular signal in a misfolding disorder.