TRPM4 has been described as the nonselective cationic channel regulated by internal Ca²⁺ ([Ca²⁺]_i) and required for regulating Ca²⁺ oscillations. Here we examined whether and how TRPM4 channels are involved in store-operated Ca²⁺ (SOC) entry in the HEK 293 cell by using RFP-tagged full length TRPM4 and its variant TRPM4a, which was deleted the first part of 174 amino acid residues in N-terminus. Confocal miscroscopic data showed that TRPM4 was predominantly localized in plasma membrane and TRPM4a was rarely detected in the membrane but densely in endoplasmic reticulum and Golgi apparatus. SOC influx was examined by exposure to 2.5 mM Ca²⁺ following stimulation by 100 μM UTP for 2~3 min in order to deplete the internal Ca²⁺ store via endogenous P2Y receptor-G_q/11-InsP₃ signaling pathway in HEK 293 cell. Externally applied 100 μM UTP caused [Ca²⁺]_i transients in non-transfected and both TRPM4- and TRPM4a-expressed cells under the Ca²⁺-free condition. Subsequent exposure to Ca²⁺ elicit a second [Ca²⁺]_i rise in non-transfected and TRPM4a expressed cells but not in TRPM4-expressed cells. Nonselective whole-cell currents were hardly detected in TRPM4-expressed cells, suggesting that TRPM4 channels interfere with SOC entry pathway(s) such as Ca²⁺-permeable TRP channels endogenously expressed in HEK 293T cells. Taken together, these results show that TRPM4 can possibly inhibit store-operated Ca²⁺ entry and its first part of N-terminus is critical for the translocation of TRPM4 to the membrane.