Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+-permeable nonselective cation channel that is stimulated by oxidative stress and specifically activated by intracellular ADP-ribose. Because TRPM2 is highly expressed in immunocytes, a role of this channel in inflammation processes has been proposed. The aim of the current study was to determine the function of TRPM2 in LPS-induced cytokine production of human monocytes. Incubation of human primary monocytes with LPS resulted in an upregulation of TRPM2 mRNA, protein, and of ADP-ribose–induced membrane currents. By using short hairpin RNA to downregulate TRPM2 expression in THP-1 monocytes, we demonstrate that TRPM2 is required for the LPS-induced production of IL-6, IL-8, IL-10, and TNF-α. Application of LPS led to a time-dependent increase in intracellular Ca 2+ concentrations in THP-1 cells that was clearly reduced by downregulation of TRPM2. Omission of extracellular Ca 2+ strongly decreased TNF-α production in TRPM2-expressing cells. Thus, TRPM2-mediated Ca 2+ entry is a central mechanism for LPS-induced cytokine production in monocytic cells. The identification of TRPM2 as a major player in this LPS-dependent process makes it a promising tool in modulating monocyte functions.