Lung ischemia-reperfusion (I/R) injury is a critical complication following a lung transplant, cardiopulmonary bypass, pulmonary embolism, and trauma. Immune cells and their effector functions are involved in the lung I/R injury. Store-operated calcium channels (SOCC) are highly Ca2+-selective cation channels and have crucial effects on the immune system. It has been indicated that BTP2, a potent SOCC blocker, could inhibit pro-inflammatory cytokine production from immune cells both in vitro and in vivo. Therefore, this study was conducted to investigate the beneficial effects of BTP2 on lung I/R injury in Sprague-Dawley (SD) rats. The left lungs of male SD rats underwent ischemia for 60 min and reperfusion for 2 h. Treated animals received BTP2 4 mg/kg or 10 mg/kg intraperitoneally 30 min before the ischemia. The results revealed that pretreatment with BTP2 markedly attenuated I/R injury-induced pulmonary edema, microvascular protein leakage, neutrophil infiltration, adhesion molecules, cytokine production (e.g., ICAM-1, TNF-alpha, IL-1 beta, and IL-2), and the transcription factor nuclear factor of activated T cells c1 nuclear translocation in the lung tissue. These findings indicate that BTP2 can be a potential therapeutic drug for lung I/R injury and suggest that SOCC may play a critical role in lung I/R injury.