Preliminary literature reports suggest the possibility that, in an allergic patient, a previously positive allergological test may turn negative after a long period of time with no further exposure to the specific allergen. The aim of this study was to evaluate the rate by which a previously positive skin test or RAST may turn negative in a group of patients allergic to penicillin if no further exposure to the specific allergen occurs. Sixty-three patients allergic to penicillin (48 with type I allergy and 15 with type IV allergy) were enrolled in a long-term, prospective, follow-up study, undergoing a successive complete allergological testing within 6 years of the first positive examination. During the follow-up period, skin tests progressively became negative in 28 (58.3%) type I allergic patients and in only one (6.7%) subject with type IV allergy. Similarly, the positive RAST turned negative in as many as 13 subjects (43.3% of cases). The cumulative skin test positivity (type I allergy) was significantly lower than that of patch tests (type IV allergy) (chi 2 = 10.4; d.f. = 1; p < 0.005, Logrank test). No significant difference in the progressive rate of decrease in skin test and RAST cumulative positivity was observed in the 30 patients showing both RAST and skin test positivity on entering the follow-up study. Our results provide strong evidence that a positive allergological test performed in a drug-allergic patient may become negative with time, in the absence of further exposure to the specific antigen. A negative allergological test cannot, therefore, rule out the immunological basis of a drug sensitivity. This is why we always suggest advising patients with a personal history of drug hypersensitivity against any further administration of the responsible drug, even in the presence of a completely negative allergological examination.