Intensive longitudinal investigations of breeding and growing pig populations in two multiple-site swine production systems were conducted in NC, USA. Five cohorts of sows and individually identified growing pigs from their litters were serially sampled in order to determine the prevalence and serotypes of Salmonella enterica in each stage of production based on fecal culture. In addition to fecal samples, feed and environmental samples were obtained. Fifteen different serotypes were isolated from the two systems, the most frequently isolated serotypes were S. typhimurium var Mbandaka and S. typhimurium var Copenhagen. Pig prevalence estimates ranged from 0 to 48.1%. Environmental contamination was frequently encountered despite cleaning and disinfection. Feed was rarely (2/800, 0.25%) identified as S. enterica positive. We observed highly variable patterns of S. enterica prevalence and serotype profiles within cohorts over time and among cohorts within systems. These observations indicate that point estimates of S. enterica prevalence and serotypes cannot be considered as reliable indicators of the S. enterica status of farms, and that uncontrolled studies of interventions to control S. enterica may yield misleading results. These findings are critical to the design of epidemiological studies of S. enterica on swine farms and may suggest that cohort level, as opposed to farm or company level events or management practices, may be important as potential risk factors for S. enterica fecal shedding in market age pigs.