There is accumulating correlational evidence that the effect of specific types of reading instruction depends on children's initial language and literacy skills, called child characteristics x instruction (CxI) interactions. There is, however, no experimental evidence beyond first grade. This randomized control study examined whether CxI interactions might present an underlying and predictable mechanism for explaining individual differences in how students respond to third-grade classroom literacy instruction. To this end, we designed and tested an instructional intervention (Individualizing Student Instruction [ISI]). Teachers (n = 33) and their students (n = 448) were randomly assigned to the ISI intervention or a vocabulary intervention, which was not individualized. Teachers in both conditions received professional development. Videotaped classroom observations conducted in the fall, winter, and spring documented the instruction that each student in the classroom received. Teachers in the ISI group were more likely to provide differentiated literacy instruction that considered CxI interactions than were the teachers in the vocabulary group. Students in the ISI intervention made greater gains on a standardized assessment of reading comprehension than did students in the vocabulary intervention. Results indicate that CxI interactions likely contribute to students' varying response to literacy instruction with regard to their reading comprehension achievement and that the association between students' profile of language and literacy skills and recommended instruction is nonlinear and dependent on a number of factors. Hence, dynamic and complex theories about classroom instruction and environment impacts on student learning appear to be warranted and should inform more effective literacy instruction in third grade. (Contains 1 note, 9 tables, and 4 figures.)