Leptospirosis is a world-wide diffused anthropozoonosis due to many strains of Leptospira. Initial symptoms may be mild, although in many cases severe systemic symptoms, including high fever, hypotension, etc. may be present since the beginning. In these latter circumstances, the diagnosis of leptospirosis can be very difficult because of the complexity of clinical picture especially when the history is lacking or incomplete. A case report of a 45 year-old man admitted to the hospital after severe jaundice and fever of unknown origin associated to altered mental status, renal failure and hypoxemia is presented. Because of the presence of septic shock and severe respiratory failure, the patient was transferred to the intensive care unit. The diagnostic hypothesis, based on clinical history, was confirmed by laboratory tests (leptospiral IgM antibodies detection). Therapeutical approach with the use of selected antibiotics (penicillin 24,000,000 U for day) and therapy of septic shock led to improvement of the patient's clinical conditions who was then transferred to a regular medical ward.