Objective: Methyl-mercury (MeHg) was discharged from a chemical factory in Minamata, and consequently spread throughout the Shiranui Sea in Kumamoto, Japan. Although many studies have focused on MeHg-induced neurological disorders, the association between MeHg and malignant neoplasms has not been adequately investigated. Therefore, we explored this association using the age standardized mortality ratio (ASMR) in an ecologic study over a wide area allowing for a long empirical induction period. Methods: The subjects were residents in areas around the Shiranui Sea. We divided these areas into exposure groups 1 (Minamata and Ashikita regions) and 2 (Amakusa region). Exposure group 1 was contaminated from the late 1930s, and exposure group 2 was contaminated from the late 1950s. In addition, exposure group 1 was contaminated more heavily than exposure group 2. There were 92,525 and 152,541 residents in each group in 1960, respectively. We analyzed the cancer ASMR in both exposure groups using data from two reference populations (Japan and Kumamoto prefecture) from 1961 to 1997. There were 94,301,494 and 1,856,192 people in each reference group in 1960, respectively. We abstracted population and mortality data from the censuses and the vital statistics of the prefecture and Japan. Results: An increased leukemia ASMR and a decreased gastric cancer ASMR were observed in both exposure groups, while other ASMRs were around unity and less precise. Furthermore, the leukemia ASMRs were elevated differently between the two exposure groups: the leukemia ASMR was already elevated early in the study period in exposure group 1 and increased gradually in exposure group 2. Conclusions: While the negative association between MeHg and gastric cancer might be explained by salt intake, the positive association between MeHg and leukemia could not be explained by potential confounders. Despite some limitations mainly due to its ecologic design, this study indicates the necessity of an individual-level study evaluating the association between MeHg and leukemia in regions with exposure to MeHg. © Springer-Verlag 2007.