An investigation was conducted into the potential risk factors associated with mortality during an outbreak of Streptococcus suis disease in weanling pigs. Retrospective data were used to identify both sow- and pig-level factors that could result in increased risk of mortality. A Cox’s hazard regression model identified pigs originating within certain litters that appeared to be at increased risk. Risk for individual pigs increased if a littermate died or if the pig originated from a litter where the sow’s previous litter had low mortality. During the outbreak, a proportion of litters were vaccinated using an autogenous bacterin. Direct, indirect, total, and overall measures of vaccine effectiveness were evaluated using Cox’s hazard and binomial regression models. Measures of total (~27%) and overall (~21%) vaccine effectiveness had the largest estimated magnitude, with no evidence of direct effectiveness. Overall, there is potential for benefits of vaccination despite lack of evidence of direct effectiveness.