Clopidogrel hypersensitivity affects up to 6% of treated patients, often leading to discontinuation of the drug. Conventional desensitization protocols incorporate a washout period off medication that may be problematic after percutaneous coronary intervention because premature discontinuation of dual antiplatelet therapy is a major risk factor for stent thrombosis. The purpose of this study was to evaluate a strategy for treating clopidogrel hypersensitivity without drug interruption using corticosteroids and antihistamines to facilitate development of physiologic tolerance. The study population consisted of 25 consecutive patients who developed clopidogrel hypersensitivity after percutaneous coronary intervention and were managed with suppressive therapy using corticosteroids and antihistamines. Treatment success (resolution of hypersensitivity symptoms without interrupting clopidogrel) was assessed, in addition to duration of clopidogrel therapy and adverse cardiac events during late follow-up (mean 670 ± 630 days). The cohort included 19 men and 6 women with a mean age of 62 ± 9 years. Drug-eluting stents were used in 16 patients (64%). Clopidogrel hypersensitivity occurred 6 ± 2 days after drug initiation. Treatment included corticosteroids (5 patients), antihistamines (5 patients), or corticosteroids and antihistamines (15 patients). Patients treated with corticosteroids received tapering courses for a mean of 10 ± 8 days. Treatment was successful with sustained symptom resolution in 22 of 25 patients (88%). Clopidogrel therapy was continued in successfully desensitized patients for 417 ± 369 days and in patients with drug-eluting stents for 529 ± 376 days. There were no deaths, myocardial infarctions, or stent thrombosis during extended follow-up. In conclusion, clopidogrel hypersensitivity can be successfully treated using short-course corticosteroids and antihistamines without interrupting drug therapy. This technique enables long-term continuation of clopidogrel and confers a low risk of adverse cardiac events.