BACKGROUND During the past 2 1/2 years we observed six patients who had a reactive serology for syphilis, of which four developed widespread noduloulcerative and two vesiculonecrotic lesions. The purpose was to report the occurrence of lues maligna, a rare form of secondary syphilis, in five patients infected with the human immunodeficiency virus (HIV) and in one patient with risk factors for infection. METHODS Tzanck preparations, viral cultures, and skin biopsies were performed to evaluate the etiology of the lesions. RESULTS Syphilis serology titers ranged from 1:32 to 1:128 and in one instance was as low as 1:8. Such titers can also be found in patients with the latent form of syphilis. Therefore, confirmation of the clinical diagnosis of lues maligna was dependent on skin biopsies that were compatible with secondary syphilis and negative viral studies that excluded varicella, disseminated varicella-zoster or herpes simplex. Lues maligna takes an aggressive course in HIV-infected patients since four of the patients required hospitalization and the two patients who refused to complete treatment, subsequently developed more severe skin and constitutional symptoms. CONCLUSIONS HIV-infected patients are at risk for developing lues maligna. Despite its malignant presentation, lues maligna lesions respond rapidly to treatment with penicillin. Secondary syphilis should be added to the list of diseases known to be more aggressive in HIV-infected patients.