Abstract Background/Purpose Mucopolysaccharidosis I (MPS I) is a rare lysosomal storage disorder caused by deficiency of α-L-iduronidase, which results in progressive multisystemic disease. Patients with MPS I often require multiple common and uncommon surgeries and are at risk for surgical and anesthetic complications because of respiratory and cardiac disease. Surgery often precedes diagnosis; thus, surgeons and anesthesiologists may be unaware of potential risks. Methods We analyzed data from the MPS I Registry, a voluntary observational database, for deaths occurring within 1 month of a surgical procedure among the 932 patients enrolled as of July 2010. Results Among the 196 deceased patients, 186 reported 1 surgery or more, and 32 had 1 surgery or more within 1 month of death, including 20 who had 1 surgery or more within 10 days of death. Surgeries before death included hernia repair, central line placement, spinal surgery, tracheostomy, and ventriculo-peritoneal shunt. Most patients (28/32) had severe MPS I (Hurler), and 20 of 32 patients (all Hurler) died at 3 years or younger. In 6 of 32 patients, surgery was directly noted in the cause of death, including 4 patients with an attenuated form of MPS I. Conclusions Patients with mucopolysaccharidosis have a high postoperative mortality because of underlying respiratory and cardiac diseases.