Background Isosulfan blue 1% is a dye used in medical procedures such as lymphangiography and sentinel lymph node biopsy. Anaphylactic reactions to this dye have been rarely reported. Objective We are reporting two patients who experienced anaphylaxis after subcutaneous administration of isosulfan blue. Methods Two female patients with breast cancer were evaluated by our allergy service after suspected intraoperative anaphylactic episodes during sentinel lymph node biopsies in which they had received isosulfan blue 1% for the purpose of visualization of the lymph vessels. In the first case, the patient suffered hypotension and hypoxia requiring intubation. In the second case, the patient suffered prolonged hypotension. Both patients recovered without sequelae. The patients were seen in our clinic, and skin tests were performed to isosulfan blue in addition to other agents the patients had received during anesthesia. Results In both cases, the patients demonstrated positive skin tests to isosulfan blue. Neither patient had positive skin tests to any other agent used for skin testing. Isosulfan blue skin tests were performed in nine control subjects and all skin tests in the control subjects were negative. Conclusions Isosulfan blue may be a cause of anaphylactic reactions and this seems to be an immunoglobulin E-mediated event as confirmed by positive skin tests.