This study examines the initial word reading performance of fourth-grade struggling readers and the extent to which differing levels of word reading performance at pretest influenced their response to reading interventions. A large group of students with significant reading comprehension difficulties (N = 481) were classified into three clusters of word reading proficiency based on their pretest performance: (a) very low, (b) low, and (c) near adequate. We examined their performance on several academic, language, and executive functioning measures at the beginning of the year and their reading comprehension performance at the beginning of year and after 1 year of reading intervention to examine how each cluster responded to instruction. Results from a discriminant function analysis indicated that performance on five pretest variables were meaningful predictors of word reading proficiency cluster membership: phonological processing, writing fluency, math calculation, math fluency, and reading efficiency and comprehension. Results also demonstrated that word reading proficiency at pretest was related to response to intervention on reading comprehension measures. Students in the very low word reading proficiency cluster showed minimal response to intervention whereas the near-adequate word reading cluster demonstrated greatest response to intervention. These results suggest word reading is a critical predictor of response to intervention for students with significant comprehension problems in the upper elementary grades and that students with the most substantial word reading problems may require more intensive and specialized treatments than students with greater word reading performance to show meaningful progress in reading.