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Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved by the US Food and Drug Administration for the treatment of colorectal (CRC) and head and neck (H&N) cancers. Hypersensitivity-infusion reactions (HIRs) confer moderate morbidity and potential mortality. HIRs have a wide geographic incidence with few identifiable risk factors. Limited data regarding risk-reduction interventions for HIR or post-HIR retreatment are available. All patients treated with cetuximab at a single Veterans Affairs facility were monitored for development of HIRs, with baseline clinical, demographic, and supportive care data recorded. All received standard premedication based on cohort assignment. A total of 51 consecutive patients (30 CRC; 21 H&N) received at least one dose of cetuximab. Grades II-IV HIRs occurred in 14 patients (27%; 6 grade II, 6 grade Ill, 2 grade IV). There was no grade V HIR. All HIRs occurred during the first infusion. There were no differences between age, race, diagnosis, stage, concurrent chemotherapy, or radiotherapy with cetuximab, allergy history, or military service era of patients developing HIRs versus those who did not.There were no identifiable risk factors that predicted the severity of HIR. Neither premedication modifications (P = 0.34) nor bronchodilator use (P= 0.12) impacted the incidence or severity of HIR. A cetuximab test dose successfully elicited an HIR and resulted in an 87% cost savings. None of five patients receiving subsequent retreatment with anti-EGFR MoAb had recurrence of an HIR. An HIR during cetuximab infusion can be a serious and underestimated toxicity. The relatively high incidence reported here is consistent with that previously identified in the Southeastern United States. No clinical, demographic, or historic variables reliably predicted HIR in our population. Use of a test dose to elicit a HIR appears to be feasible and cost-effective. Use of panitumumab after a cetuximab HIR in select patients with CRC appears to be feasible and safe.