Purpose: We examined the effectiveness of a multistrategy inference intervention designed to increase inference making and reading comprehension for middle-grade struggling readers. Method: A total of 66 middle-grade struggling readers were randomized to treatment (n = 33) and comparison (n = 33) conditions. Students in the treatment group received explicit instruction in 4 inference strategies (i.e., clarification using text clues; activating and using prior knowledge; understanding character perspectives and author's purpose; answering inferential questions). In addition, narrative and informational texts were carefully chosen and sequenced to build requisite background knowledge to form inferences. Intervention was delivered in small groups of 3 students for 10 days of instruction. Results: One-way analysis of covariance models on outcome measures with the respective pretest scores as a covariate revealed significant gains on a proximal measure of Egyptian-content knowledge (g = 1.37) and on a standardized measure of reading comprehension—i.e., Wechsler Individual Achievement Test–Third Edition Reading Comprehension (g = 0.46). Conclusion: The moderate effect on a standardized measure of reading comprehension provides preliminary evidence for the effectiveness of this multistrategy inference intervention in improving reading comprehension of middle-grade struggling readers.