Leprosy is caused by the well-known Mycobacterium leprae and the newly discovered M lepromatosis. Here, the authors describe 2 cases of leprosy with unusual clinical presentation caused by M lepromatosis. The patients, a 32-year-old man and a 50-year-old woman, both of Mexican origin, manifested high fever, lymphadenopathy and florid skin lesions in the form of erythema nodosum and Lucio's phenomenon as the first clinical presentation. Heavy infiltration of acid-fast bacilli was identified in the tissues that led to the diagnosis of lepromatous leprosy or diffuse leprosy. The patients were treated with multidrug regimen and responded appropriately. From the lymph node tissue, the authors showed the bacillus to be M lepromatosis, not M leprae as presumed previously, by differential polymerase chain reactions and analysis of gene sequences. These cases add to the growing studies on this organism, expand its endemic regions in Mexico and provide more clinical insight.