From 1971 through August 1978, 778 patients underwent penicillin skin testing. Each patient gave a history of previous penicillin allergy. The skin-test reagents consisted of (1) fresh solutions of commercially prepared penicillin G (PEN G), ampicillin (AMP), and methicillin (METH); (2) polylysine conjugates of the major antigenic determinants of each of the three drugs: and (3) alkaline hydrolysates of each drug. A total of 108 (14%) patients showed positive reactions to one or more of the reagents. Certain patients showed reactivity to many reagents, whereas others reacted selectively to only one or two reagents. Addition of reagents of AMP and METH resulted in a greater number of positive reactors than when reagents of PEN G alone were used. Of the group whose skin tests were negative, 290 (43%) were later treated with penicillin, twelve of these (4.1%) had allergic reactions. Eight of the group of whose skin tests were positive were subsequently treated, and four of these (50%) had allergic reactions again. A group 151 patients whose skin tests were negative and 27 patients whose skin tests were positive were treated with a cephalosporin. Only two patients had allergic reactions to the drug: both had had negative skin tests to penicillin. We conclude that the risk of subsequent allergic reactivity to penicillin is much lower if the skin tests are negative than if positive, that testing with semisynthetic penicillins increases the number of skin-test reactors, and that the incidence of allergic reactions is low in patients treated with cephalosporin.