This experimental study aimed to influence reading comprehension skills through the development of one or both components of the Simple View of Reading (decoding and listening comprehension), by using a differentiated instruction approach. Reading comprehension skill gains were compared in an intervention group versus a control, after the delivery of a program designed to target one or both of such components. Fifty-four children from two 1st grade classrooms in a public school in Mexico were screened for difficulties in decoding and listening comprehension at the end of the school year. At the beginning of 2nd grade, 27 students identified with difficulties were randomly assigned to either an intervention (n = 14) or a control group (n = 13). Students selected for the targeted intervention attended the sessions aimed at their specific needs: five students with poor decoding only received the Phonological and Orthographic Awareness sessions of the intervention (9 sessions); seven students with poor listening comprehension only attended the Oral Vocabulary sessions (5 sessions); two students with mixed difficulties attended the full program (14 sessions). A 2 × 2 mixed analysis of variance showed that the interaction between the Time and Group variables had a significant effect, i.e. students in the intervention group had significantly higher scores in the post-test evaluation with respect to their baseline and compared to the growth observed in the control group. Results are discussed concerning their implications for teaching practices and for the use of strategies that target reading specific difficulties in students using both oral and written language.