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Introduction Rash can be one of the symptoms in acute infectious mononucleosis. According to the classical literature sources, drug-induced rash can be associated with synthetic penicillin and Epstein-Barr virus itself. Nowadays, a lot of case reports point to the development of rash after the administration of other groups of antimicrobials. Clinical and laboratory signs and the administration of antimicrobials in acute Epstein-Barr virus infection have been correlated with the development of rash. Material and Methods This retrospective-prospective study (2007-2010) included 243 patients hospitalized for acute infectious mononucleosis at the Department for Infectious Diseases, Clinical Center of Vojvodina, of whom 51 had rash and 192 were without it. Epstein-Barr virus infection was confirmed by ELISA IgM EBVVCA in all patients. Results Student's t-test did not show a significant difference between the age, gender, duration of symptoms, leucocytes count, absolute lymphocytes count, alanine aminotransferase, aspartate aminotransferase among patients with or without rash. X² test did not show a significant difference among the patients treated by synthetic or pure penicillin, macrolids and 1st and 2nd generation cephalosporins. However, if we compare all these antimicrobials, there is a significant difference between them and 3rd generation cephalosporins. Only two patients developed rash without antimicrobials. Conclusion According to our results, rash developed independently of the clinical course of disease. Previous conclusion that synthetic penicillin produces rash seems to be not true, because there are many patients who were treated with them but did not develop rash. All antimicrobials can be associated with rash, but 3rd generation cephalosporins seem to produce rash less frequently than the others. [ABSTRACT FROM AUTHOR]