This study demonstrates the generalization of previous laboratory results showing the benefits of self-explanation reading training (SERT) to college students' course exam performance. The participants were 265 students enrolled in an Introductory Biology course, 59 of whom were provided with SERT training. The results showed that SERT benefited students who began the course with less knowledge about science, but did not benefit students with greater prior science knowledge. Moreover, across the three exams in the course, low-knowledge students who received SERT performed as well as high-knowledge students, whereas low-knowledge students without SERT performed more poorly than high-knowledge students. Hence, instruction on how to self-explain and use comprehension strategies allowed low-knowledge students to overcome their knowledge deficits. These results provide further evidence that self-explanation in combination with instruction and practice using comprehension strategies helps students to more effectively process and understand science. [This article was published in "Discourse Processes," v54 n7 p479-492 2017 (EJ1154551).]