Practitioners are increasingly expected to provide reading instruction to students with intellectual disabilities to help them become literate. Whereas explicit, systematic reading instruction is effective at preventing reading difficulties for most young children, its effectiveness for children with intellectual disabilities remains unclear. The study's purpose was to explore this issue by identifying important child characteristics predictive of differential growth in targeted reading skills in response to a reading intervention that targeted phonological awareness, letter sound knowledge, and reading of decodable, sight, and nonsense words. One-on-one instruction was provided to 24 children with Down syndrome between the ages of 7 and 16 years. Results indicate that a majority of children demonstrated statistically significant growth on letter sounds, taught sight words, and decodable words. Children with Down syndrome who entered the study with more advanced word identification skills made greater gains in decodable word reading; those with more advanced phoneme segmentation skills made greater gains in nonsense word reading. Overall, findings suggest that incorporating elements of explicit, systematic reading instruction into interventions for children with Down syndrome may be beneficial for many.