In order to address the hypothesis that coxsackievirus B5 is a cause of insulin-dependent diabetes mellitus (IDDM), the incidence of IDDM was examined following an epidemic of coxsackievirus B5 in Jefferson County, Alabama. Incidence estimates were obtained from a registry of IDDM which was maintained in the county since 1979. A total of 266 cases were diagnosed (69 black and 197 white individuals less than 20 years of age) between 1979 and 1988. Significant increases in incidence were observed in both races, corresponding temporally to the epidemic of coxsackievirus B5 which occurred in 1983. The overall incidence in the year beginning July 1983, the month of the first isolation of coxsackievirus B5, was 18.4/100,000 person-years, an excess of 6.7/100,000 person-years over the average annual incidence for the previous 4 years. The increase was greatest in females and among all children aged 10-14 years. This study provides support for the role of coxsackievirus B5 in the multifactorial etiology of IDDM, and suggests a possible basis for the increased incidence of IDDM reported around the world in the early 1980s. Am J Epidemiol 1991; 133:1024-31. © 1991 by The Johns Hopkins University School of Hygiene and Public Health.