Hyaluronidase is an enzyme that has temporary and reversible enzymatic effects on the matrix of connective tissue. When added to local anesthetics in pain treatments, it enhances their infiltration and dispersal into tissues. It is widely used in anesthesia for ocular, dental, and plastic surgery. Reports of drug hypersensitivity to hyaluronidase are rare and are usually confined to peribulbar or retrobulbar anesthesia during ophthalmic surgery. However, few reports exist on adverse drug reaction after epidural injection. We have observed two patients experiencing anaphylactic shock caused by hyaluronidase following epidural injection. Most of the patients with a hypersensitivity to hyaluronidase had one previous uneventful injection containing hyaluronidase, implying that sensitization had taken place. However, hypersensitivity occurring at the first administration is possible. A positive skin test can help establish the diagnosis. Although rare, the possibility of an allergic reaction to hyaluronidase should be considered even in patients with no known previous exposure.