Prior studies suggest that teaching reading strategies promotes reading comprehension in adolescents who have difficulties with reading comprehension, yet the results of those studies are mixed. Individual differences in students’ vocabulary knowledge may explain these mixed results. This article examines to what extent vocabulary knowledge influences the effect of a two-year intervention program focused on teaching reading strategies to adolescents with low academic achievement in the Netherlands. We hypothesized that students (N = 310) with different levels of vocabulary knowledge would respond differently to the treatment, given that vocabulary knowledge is an important factor in reading comprehension. Results showed that vocabulary knowledge moderated the effect of the treatment, suggesting that low vocabulary knowledge negatively affected the impact of an intervention focused on reading strategies. Vocabulary knowledge, thus, emerges as a prerequisite for the successful leveraging of a reading strategy intervention. Students with low vocabulary knowledge may experience cognitive overload when attempting to apply newly learned reading strategies while simultaneously trying to find out the meaning of multiple unfamiliar words needed for successful application of reading strategies.