Allergic reactions to oxaliplatin (Eloxatin) may be sufficiently severe to prevent patients from continuing treatment. Oxaliplatin is a key drug that improves the survival of colorectal cancer patients; however,a uniform approach to prevent allergic reactions in patients using this drug has not been established. We investigated the safety and efficacy of our own preventive strategy in colorectal cancer patients receiving the 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen. Each patient received the primary prevention regimen before oxaliplatin infusion during the first cycle and diphenhydramine after cycle 4. Patients who experienced grade 1 or 2 allergic reactions subsequently received the secondary prevention regimen with a higher dose of dexamethasone and prolonged oxaliplatin infusion to allow continued treatment. Oxaliplatin was discontinued in patients with grade 3 or 4 allergic reactions. Forty-eight patients (17.6%) developed allergic-reactions,and 30 patients underwent retreatment with the secondary prevention regimen. Nineteen patients (63.3%) showed no reactions during at least 2 cycles; most could be treated for 4 months longer than could patients who did not respond to secondary prevention. This preventive strategy was both safe and effective, allowing patients to continue treatment without detriment to their quality of life.