Abstract: Amitriptyline is a tricyclic antidepressant widely used in clinical practice for the treatment of an-xiety and depression and chronic pain. These drugs have a multifaceted effect on cellular processes. One of their targets is sigma-1 receptors. Sigma-1 receptors are molecular chaperones located in the membrane of the endoplasmic reticulum; they are characterized by a unique structure and pharmacological profile. Sigma-1 receptors regulate many cellular processes in health and disease, including processes of Ca2+ signaling. Using Fura-2AM fluorescent Ca2+ probe, we showed for the first time that sigma-1 receptor agonist, the antidepressant amitriptyline, significantly suppresses Ca2+ mobilization from the intracellular Ca2+ stores and subsequent store-dependent Ca2+ entry into cells caused by inhibitors of endoplasmic Ca2+ ATPases thapsigargin and cyclopiazonic acid, as well as the disulfide-containing immunomodulators glutoxim and molixan, in rat peritoneal macrophages. The results indicate the participation of sigma-1 receptors in the complex signaling cascade caused by glutoxim or molixan, leading to an increase in intracellular Ca2+ concentration in macrophages. Data also indicate that sigma-1 receptors participate in the regulation of store-dependent Ca2+ entry in macrophages.