Background Diabetic macular edema (DME) causes severe vision loss among patients with diabetes mellitus (DM). We aimed to investigate systemic and local diseases associated with the development of DME among a Japanese population. Methods A total of 3.11 million Japanese subjects who were registered in the database of the Japan Medical Data Center from 2005 to 2014 were analyzed. Subjects with DM were defined as individuals who had been prescribed any therapeutic medications for DM, and associated diseases were analyzed. The periods analyzed were one year before the development of DME among patients with DME and one year before the last visit to an ophthalmic clinic among patients without DME. Results A total of 17,403 patients with DM satisfied the inclusion and exclusion criteria, and 420 patients developed DME. Univariate analysis revealed significant associations between 55 diseases, including 39 systemic and 16 local diseases, and DME development. The logistic analysis identified 21 systemic diseases and 10 local diseases as significant factors associated with DME development. Various types of systemic and local diseases were associated with DME development. Conclusion Subjects with DM who present these risk factors must be carefully monitored to prevent visual impairment.