Sigma-1 receptors are ubiquitous multifunctional ligand-operated molecular chaperones in the endoplasmic reti-culum membrane with a unique history, structure, and pharmacological profile. Sigma-1 receptors bind ligands of different chemical structure and pharmacological effect and modulate a wide range of cellular processes in health and disease, including Ca2+ signaling processes. To elucidate the involvement of sigma-1 receptors in Ca2+ signaling processes in macrophages, the effect of sigma-1 receptor ligands, phenothiazine neuroleptics chlorpromazine and trifluoperazine, on Ca2+ responses induced by endoplasmic Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid, as well as by disulfide-containing immunomodulators glutoxim and molixan, was investigated in rat peritoneal macrophages. Using Fura-2AM microfluorimetry we have shown for the first time that chlorpromazine and trifluoperazine suppress both phases of Ca2+ responses induced by glutoxim, molixan, thapsigargin and cyclopiazonic a-cid. The data obtained indicate the involvement of sigma-1 receptors in the complex signaling cascade triggered by glutoxim or molixan and leading to intracellular Ca2+ concentration increase in macrophages. The results also suggest the involvement of sigma-1 receptors in the regulation of store-dependent Ca2+ entry in macrophages.