Informed by theories of reading comprehension and prior reviews of reading comprehension intervention, this meta-analysis uniquely contributes to the literature because it describes the relative effects of various approaches to comprehension intervention for struggling readers in Grades 3 through 12. Findings from 64 studies demonstrate significant positive effects of reading comprehension intervention on comprehension outcomes (g = 0.59, p < 0.001, 95% confidence interval [CI] [0.47, 0.74], [tau][superscript 2] = 0.31). A metaregression model indicated significantly higher effects associated with researcher-developed measures, background knowledge instruction, and strategy instruction, and significantly lower effects associated with instructional enhancements. Grade level, metacognitive approaches, and study quality did not moderate effects. Findings support the use of background knowledge instruction and strategy instruction to support comprehension of struggling readers in upper elementary and beyond.