Clinical case We present the case of a 32 year-old man, HIV positive in treatment, that presented to our hospital. He had erythematous papules scattered through his trunk, limbs (including palms and soles) and genitalia. He denied previous genital, oral or anal ulcer. His previous serological tests for syphilis were negative. We suspected a secondary syphilis and prescribed Benzatin G Penicillin 2.4 M IU. The patient referred to the emergency room for a flu-like reaction and worsening of the skin lesions after the injection. We performed a biopsy that confirmed the clinical diagnosis of syphilis, and the serological test came out positive (RPR 64). After the second injection of penicillin, the patient experienced a second reaction, with fever and malaise. Before the third treatment we administered prednisone for three days, and he had no reaction. The Jarisch-Herxheimer Reaction (JHR) is well known since the Middle Ages, when it was associated with mercury ointments used for the treatment of syphilis. The first literary descriptions came from Jarisch in 1895 and Herxheimer seven years later. Since then it has been described during the antibiotic treatment of various spirochete infections. It begins 2 to 8 hours after the treatment, as a flu like reaction with high fever and is sometimes associated to an aggravation of the syphilis symptoms. It usually resolves in 24 hours without treatment, but the patients usually receive antipyretic treatment. This reaction appears in 50% of primary syphilis, and up to 75% of secondary syphilis. It’s very rare in latent syphilis, but can appear in 30% of neuro-syphilis. There has been only one description of a recurrent JHR, in a patient with a late latent syphilis that had 2 JHR after 2 consecutive penicillin injections. To our knowledge it has not been described in any other syphilis patient.