Background: Histoplasmosis is a fungal disease with a worldwide distribution. Travelers returning from endemic areas with a history of exposure to fungal spores have a high risk of infection. Methods: We report four cases of acute pulmonary disease in Italian spelunkers returning from Mato Grosso, Peru. Results: Symptoms and radiologic findings were consistent with acute pulmonary illness. Laboratory data supported the hypothesis of histoplasmosis. Conclusions: Histoplasmosis should be considered in the differential diagnosis in travelers returning from endemic areas, who report a risk of exposure, and present with respiratory illness. In this setting, seroconversion may be considered diagnostic of pulmonary histoplasmosis.