Hypersensitivity reactions after endovenous ablation with cyanoacrylate are relatively common, mild, and self-limited. However, rare cases of severe hypersensitivity reactions have occurred. To date and to the best of our knowledge, only two other cases requiring vein excision have been reported, and we present the third. Even rarer are cases with severe reactions featuring cyanoacrylate extravasation with skin perforation. In the present report, we describe the second case of skin perforation after successful cyanoacrylate endovenous glue embolization. The mechanism of these severe hypersensitivity reactions is unknown. Clinicians should to consider this as a possible complication when using cyanoacrylate. Although rare, patients should also be advised of this adverse event when considering this alternative.