Research supports the efficacy of intensive literacy instruction for children with moderate intellectual disabilities and Down syndrome (DS). However, much of the literature features measures closely aligned with evaluated interventions. Despite their increasing role in instruction, curriculum-based measures (CBM) are rarely featured in reading studies involving DS. Increasing the use of CBM in research has the potential to provide insight into the effectiveness of intervention and address concerns regarding the utility of approaches predicated on CBM. This single-case design study used CBM to examine the performance of children with DS (N = 17) who had largely exhibited gains on intervention-aligned measures following an intensive reading intervention. Results of multilevel modeling were mixed, with significant (p < 0.05) effects relegated to letter- and first-sound fluency. No more than 29% of participants met goals created using a procedure derived from CBM. Findings have implications for future studies and implementation of literacy interventions for children with DS.