Reading for meaning is one of the most important activities in school and everyday life. The simple view of reading (SVR) has been used as a framework for studies of reading comprehension in individuals with Down syndrome (DS). These tend to show difficulties in reading comprehension despite better developed reading accuracy. Reading comprehension difficulties are influenced by poor oral language. These difficulties are common in individuals with DS and autism spectrum disorder (ASD), but they have never been compared directly. Moreover, the components of reading for comprehension have rarely been investigated in these populations: a better understanding of the nature of reading comprehension difficulties may inform both theory and practice. The aim of this study was to determine whether reading comprehension in the two populations is accounted for by the same component skills and to what extent the reading profile of the two atypical groups differs from that of typically developing children (TD). Fifteen individuals with DS (mean age = 22 years 4 months, SD = 5 years 2 months), 21 with ASD (mean age = 13 years 2 months, SD = 1 year 6 months), and 42 TD children (mean age = 8 years 1 month, SD = 7 months) participated and were assessed on measures of receptive vocabulary, text reading and listening comprehension, oral language comprehension, and reading accuracy. The results showed similar levels in word reading accuracy and in receptive vocabulary in all three groups. By contrast, individuals with DS and ASD showed poorer non-word reading and reading accuracy in context than TD children. Both atypical groups showed poorer listening and reading text comprehension compared to TD children. Reading for comprehension, investigated through a homograph reading accuracy task, showed a different pattern for individuals with DS with respect to the other two groups: they were less sensitive to meaning while reading. According to the SVR, the current results confirm that the two atypical groups have similar profiles that overlap with that of poor comprehenders in which poor oral language comprehension constrains reading for comprehension. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.