The epidemiology of Chagas disease has changed in the last decades due to migration movements, population ageing and the emergence of new transmission routes. In endemic countries, health facilities and access to healthcare are improving and T. cruzi infected patients are also benefiting from medical advances. The HIV epidemic has spread to both endemic and non-endemic areas for T. cruzi, organ transplant rates have increased recently, especially in Latin America, and other medical conditions affecting the immune system are increasing their global burden. The natural course of Chagas disease is mainly determined by the host's cellular immune response. These conditions may therefore overlap with T. cruzi infection and alter the disease's natural history which may present with atypical clinical forms and a higher associated morbidity and mortality in immunocompromised patients. The present review aims to contribute to the management of immunosuppressed patients with T. cruzi infection.