Introduction: Proton pump inhibitors (PPIs) may rarely cause thrombocytopenia. To our knowledge, only one case of lansoprazole-induced thrombocytopenia has been reported previously. Case: We report a case of a 50-year-old South Asian male who was admitted to the intensive care unit (ICU) after cardiac arrest during general anesthesia for ureteroscopy. During ICU stay, his platelet count dropped from 315×103/µL to 57×103/µL after 5 days of initiation of lansoprazole for stress-ulcer prophylaxis. After excluding other causes of thrombocytopenia; lansoprazole was stopped and his platelets recovered over the next few days. Later exposure to lansoprazole resulted in another drop in his platelet count with subsequent recovery after discontinuation of lansoprazole. A review of his home medications showed that he had been taking pantoprazole prior to hospitalization. Discussion: Thrombocytopenia has been previously reported with different PPIs. In the previously reported lansoprazole-induced thrombocytopenia, the level of certainty was not high due to lack of re-exposure. In the present case, another exposure to lansoprazole, without intention of rechallenge, reproduced the same adverse drug reaction (ADR). Although platelet-reactive antibodies testing was not available to confirm causation in this case, the Naranjo score was 8 which indicated probable causation by lansoprazole. Despite probable lansoprazole-induced thrombocytopenia, our patient had been tolerating pantoprazole. This finding highlights the different effects of individual PPIs on platelet counts in the same patient. Conclusion: Lansoprazole may cause thrombocytopenia. However, patients who develop lansoprazole-induced thrombocytopenia may tolerate other PPIs.