Background: In some diseases, penicillin G is still a treatment of choice like in sclerosing diseases of the connective tissue or in persistent scleredema of Buschke. But, suspected allergy to penicillin may limit this helpful therapy option and even leed to the exclusion of other antibiotics like cephalosporins that possibly may crossreact. Skin testing and in vitro diagnostic to detect specific sensitization to penicillin and its derivates have always to be performed but must not be conclusive. In some cases an exposition test is necessary. In single cases of medical demand a tolerance induction is needed to perform penicillin therapy for a period of time. Patients and methods: We present two patients with sclerosing diseases of the connective tissue like circumscribed sclerosis and one patient with persistent scleredema of Buschke with a positive history for penicillin. Although routine allergy testing including intracoutaneous skin testing and in vitro tests were negative, they were treated as allergic to penicillin. Penicillin was decided to be the treatment of choice so that tolerance induction with penicillin was necessary. The administration of pencillin G was achieved by performing a new scheme of tolerance induction. We started with oral doses of penicillin V and finished off with high doses of intravenously applied penicillin G. Results: In each case penicillin G was well-tolerated until the high dose of 3 × 10 7 IU/day, administered over a period of 3 weeks. In all demonstrated cases substantial clinical improvement was achieved without any complication. Conclusions: Suspected allergy to penicillin is widespread and leads to tendency to avoid all penicillin derivatives and cephalosporins as a possible way of treatment. In certain cases there is only a positive history for penicillin allergy and the diagnostic procedure remains negative. Nevertheless, these patients are suspected to be allergic to penicillin. In cases where penicillin seems to be a treatment of choice it might be necessary to perform a tolerance induction with penicillin. Here, we present a new scheme how to treat initially with penicillin V and to continue with penicillin G, and to switch from an oral to an intravenious way to manage a high-dose penicillin therapy.