Using negative binomial and multi-level Poisson models, the authors determined the statistical significance of agricultural and socio-economic risk factors for rates of reported disease associated with Escherichia coli O157 in census subdivisions (CSDs) in Alberta, Canada, 2000–2002. Variables relating to population stability, aboriginal composition of the CSDs, and the economic relationship between CSDs and urban centres were significant risk factors. The percentage of individuals living in low-income households was not a statistically significant risk factor for rates of disease. The statistical significance of cattle density, recorded at a higher geographical level, depended on the method used to correct for overdispersion, the number of levels included in the multi-level models, and the choice of using all reported cases or only sporadic cases. Our results highlight the importance of local socio-economic risk factors in determining rates of disease associated with E. coli O157, but their relationship with individual risk factors requires further evaluation.