Prospective studies of infant siblings of children diagnosed with autism spectrum disorder (ASD) provide a unique opportunity to characterize ASD as it unfolds. A critical question that remains unanswered is whether and how these children with ASD resemble other children identified from the community, including those with no family history. The purpose of this study was to compare clinical characteristics of children with ASD identified by each method (n = 86 per group), drawn from two Canadian longitudinal research cohorts. Children ascertained from a prospective cohort were less severely affected and included a larger proportion of girls, compared to the clinically referred sample. These results may have important implications for conclusions drawn from studies of high-risk and clinically referred cohorts.