This study investigated the extent to which proximity to cattle and weather events in Alberta predispose human populations to E. coli O157 disease. Cases of human E. coli O157 infection in Alberta between 2004 and 2011 were obtained from the province's Communicable Disease Reporting System and Discharge Abstract Database. Regression models based on spatial area incorporated human infection data with livestock and weather covariates. A variety of regression models were applied (i.e. least squares, spatial lag/error, Poisson, negative binomial) to test the most appropriate approach. Ratios for the total number of calves, bulls and beef cows to human population were highlighted as significant cattle density variables in all final best-fitting models. Weather variables were not significant in final regression models averaged over the full study period. Our results provide evidence of a significant association between measures of cattle density and human E. coli O157 disease in Alberta.