Brentuximab vedotin is an antibody-drug conjugate FDA-approved for the treatment of systemic anaplastic large-cell lymphoma (ALCL) that has relapsed after multiagent chemotherapy. At least 2 cases of hypersensitivity reactions to brentuximab vedotin have been reported, without attempted desensitization. This report describes a morbidly obese 32-year-old woman with ALCL that relapsed after autologous stem cell transplantation, who was treated on a phase II clinical study with brentuximab vedotin. After 1 dose, she experienced near-complete remission, but therapy was stopped because of severe drug-related toxicity. She then received 5 cytotoxic treatments and radiation, and ultimately experienced disease progression. The patient was rechallenged with brentuximab vedotin approximately 28 months after initial exposure and tolerated the dose well, but experienced a significant allergic reaction with the next dose. High-dose steroid and antihistamine prophylaxis administered 50 minutes before the subsequent brentuximab vedotin infusion was unsuccessful in mitigating this reaction. Brentuximab vedotin was successfully infused according to a rapid desensitization protocol. With progressive dose titration and supportive care, the patient tolerated this therapy. She received 11 doses through a rapid desensitization protocol and experienced a durable disease remission.