Literacy instruction for students with significant intellectual disabilities traditionally emphasizes isolated skills instruction focusing on sight words and basic vocabulary. Recent research suggests these students benefit from high-quality instruction that includes comprehension and storybook reading. This study examined the effect of a technology-based universal design for learning (UDL) approach to literacy instruction, Literacy by Design (LBD), on the reading achievement of 16 students with significant intellectual disabilities in Grades K–2. The LBD approach emphasizes reading for meaning, combining UDL-scaffolded e-books and letter and word recognition software. Nine teachers received training in research-based literacy practices. Of these, five received LBD training and implemented it four to five times weekly. Controlling for initial reading achievement, the LBD group made significantly greater gains on the Woodcock–Johnson Test of Achievement III Passage Comprehension subtest. Implications for research and practice in beginning reading instruction for children with significant intellectual disabilities are discussed.