Students gain access to mathematical tasks through reading; consequently, low-performing readers generally perform low in mathematics. High quality instruction might help students develop comprehension strategies for reading mathematics that weakens the relationship between reading and mathematics skills. The main aim of this chapter is to investigate how instructional quality might moderate the relationship between reading and mathematics achievement. Analyzing data from 37 countries and benchmark participants who applied the same sample for TIMSS 2011 and PIRLS 2011, two different models were fitted to the data for each educational system: (1) a two-level confirmatory factor analysis (CFA) model for instructional quality and the correlation between instructional quality and reading and mathematics achievement at student and class levels, and (2) a two-level random slopes model in which the slope variation across classrooms was related to class-level instructional quality. In all educational systems, there was a strong positive correlation between reading comprehension and mathematics achievement. Further, a positive relation between instructional quality and mathematics and reading achievement was observed in a number of countries. The analysis of how instructional quality moderated the relationship between mathematics and reading was inconclusive. The influence of reading comprehension on mathematics achievement was significantly moderated by instructional quality in only six countries; nonetheless, the driving hypothesis should not be rejected.