Background: A history of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with cross-intolerance to several drugs is common in some patients with coronary artery disease. We present a series of patients with acute coronary syndrome undergoing ASA desensitization prior to a possible stent to evaluate the short- and long-term efficacy and safety. The aim was to evaluate the outcomes of an ASA desensitization protocol developed by our center based on the guidelines proposed by the EAACI drug allergy expert recommendations. Methods: We developed a desensitization protocol that was based on both the patient characteristics and onset of reaction after NSAIDs, including premedication with a leukotriene antagonist and the H1-antagonist antihistamine. The clinical entities were NSAID-induced urticaria and/or angioedema in the absence of chronic spontaneous urticaria (NIUA) and NSAID-exacerbated respiratory disease (NERD). Results: A total of 23 patients were challenged or desensitized with ASA: 19 NIUA and 4 NERD. All patients tolerated the protocol at the different times of 30, 45, 90, and 120 min. The dosages of oral ASA that were given included 10, 21, 41, 81, and 162 mg (cumulative dose 315 mg). One patient reacted during the procedure and 1 during follow-up. Symptoms were limited to the skin without manifestations in other organs. All patients tolerated the required dose of ASA within 30–120 min. Those requiring urgent catheterization were desensitized within 90 min. Conclusions: Our protocol addresses challenge or desensitization with the contribution of a specialist allergist. It provides an effective, dynamic, safe, and short administration of 81 mg or higher of ASA in patients with a history of NSAID hypersensitivity with skin involvement.