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Background: Research findings on vocabulary development in children with Down syndrome are inconsistent. This study aimed to analyse the developmental trend of vocabulary growth in children with Down syndrome and the relationships between vocabulary and chronological and developmental age. Method: Children's vocabulary size was assessed by a parental report (the Italian version of the MacArthur-Bates Communicative Development Inventories [CDI]). A longitudinal study, involving 18 children with Down syndrome, and a cross-sectional study, involving 27 children with Down syndrome, were conducted. Results: The variability in children's vocabulary size increased from a chronological age of 36 months. Both vocabulary size (from 36 months) and developmental level (from 42 months) were significant predictors of lexical outcomes at 48 months. A comparison with normative data showed that children with Down syndrome had a significantly lower vocabulary size than typically developing children at the same developmental age. Conclusion: Although there are similarities with vocabulary growth in typically developing children, lexical development in children with Down syndrome appears to lag behind their cognitive development.