Promethazine is a commonly used drug in emergency departments to treat headaches and nausea. It is generally considered safe, but after thoroughly reviewing the literature, multiple instances of tissue toxicity were documented. We describe a cluster of 3 cases of promethazine-related tissue toxicity in our community. Two patients experienced extensive complications related to local necrosis, one leading to gangrene requiring amputation, and the other developing chronic pain and hypersensitivity, with a permanent decrease range of motion.