We evaluate the direct and inferential mediation (DIME) model for reading comprehension with a sample of struggling readers in Grades 3 to 5 (N = 364) in the context of a large-scale randomized controlled trial (RCT) investigating two theoretically distinct reading interventions (text processing + foundational skills [n = 117] or text processing only [n = 120]) and a control condition (n = 127). We investigate whether the intervention affects not just reading comprehension levels, but also how variables within the reading system interrelate. This approach allows the focus to shift from intervention as influencing a change in reading comprehension status to a complex set of processes. We fit structural equation models (SEMs) to evaluate the DIME model at baseline and a change model that included reading comprehension and word reading at posttest. There were no significant mean differences between groups in reading comprehension. However, significant differences emerged on the direct and indirect effects of background knowledge, vocabulary, word reading, strategies, and inferencing on comprehension across grade levels and treatment conditions. Related to treatment groups, background knowledge, vocabulary, and inferencing were significantly related to comprehension at posttest for students who received text processing and/or foundational skills interventions. The results have implications for the direct instruction of higher-order reading skills in the context of multicomponent interventions.