Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic used for the treatment or prophylaxis of Pneumocystis pneumonia and other infectious conditions. Sulfonamide derivatives have been reported to cause delayed hypersensitivity reactions, resulting in switch to less effective second-line antibiotics. Although desensitization is traditionally known to be effective in patients with immediate hypersensitivity, it is also applied to the treatment of delayed hypersensitivity in recent years. A 66-year-old female who had a history of repeated TMP-SMX-induced delayed hypersensitivity presenting as whole body rashes needed to take prophylactic dose of TMP-SMX (80/400 mg daily) before initiation of chemotherapy for multiple myeloma. Intravenous rapid desensitization was performed by using a 11-step, 4-bottle protocol from 1:1,000 to 1:1 solution for 3 hours to reach the target dose for prophylaxis. After successful rapid desensitization of TMP-SMX, 1-month prophylaxis was completed without any complications until the patient recovered normal immunity. We herein reported a case of delayed hypersensitivity reaction to TMP-SMX in an about-to-be immunocompromised host with planned chemotherapy who successfully completed 1-month prophylaxis with the drug without any complications through rapid desensitization. (Allergy Asthma Respir Dis 2015;3:155-158)