When patients allergic to penicillin develop life-endangering infection that, require treatmentwith β-lactam antibiotics, they face a fatal infection or the possibility of a fatal allergic reaction. We have approached this situation by using an oral desensitization procedure before full-dose antibiotic therapy. Thirty consecutive patients with histories of allergic reactions to penicillin, positive immediate wheal and flare skin-test reactions to penicillin determinants, and life-threatening infections were studied. Bacterial endocarditis requiring penicillin G therapy led to desensitization of 19 patients, Pseudomonas sepsis or pneumonia requiring carbenicillin treatment led to desensitization of nine subjects, and staphylococcal infections requiring therapy with a penicillinase-resistant penicillin led to desensitization of two patients. Penicillin G or carbenicillin were administered orally, beginning with 100 U or 60μg, respectively. At 15-min intervals, progressively doubled doses were given during continuous monitoring for the appearance of allergic reactions. Within 5 hr, full therapeutic doses were administered intravenously. Skin-test reactions disappeared or diminished in all 23 subjects who were retested after desensitization. Full courses of antibiotic therapy and cure of the infections were accomplished in 30 of 30 patients. No deaths, anaphylaxis, or severe acute allergic reactions occurred. Pruritic cutaneous eruptions appeared in nine patients (30%) 6 to 48 hr after the onset of therapy. One patient developed reversible nephritis 3 wk into therapy with penicillin G. The results of this sudy suggest that oral desensitization is an effective, relatively safe approach to administering β-lactam antibiotics to penicillian-allergic patients with life-threatening infections.