An epidemiological investigation was launched in several cities in southern Minas Gerais State, Brazil, considering the possibility of increased cancer incidence due to high exposure to natural radiation. First, the cancer mortality patterns were assessed to determine whether there was an increase in cancer deaths and to discuss the possible risk factors related to such an increase. The study proposed the use of a screening methodology based on standardized mortality ratio (SMR) in order to classify priority areas for future studies. Cities considered high priority for further investigation were: Andradas, for lung cancer in men (SMR = 208 (106-310)) and liver cancer in women (SMR = 403 (104-701)); Poços de Caldas, leukemia in men and women (SMR = 284 (156-412)) and SMR = 211 (111-312), respectively); Pouso Alegre, leukemia in men (SMR = 333 (127-540)) and hematological cancers in women (SMR = 257 (188-396)). Epidemiological studies are necessary to evaluate the role of radiation and other risk factors in these cancers and thus to support future preventive and control measures.