Despite the heavy reliance on textbooks in college courses, research indicates that college students enrolled in first-year science courses are not proficient at comprehending informational text. The present study investigated a reading comprehension questioning strategy with origins in clinical research based in elaboration interrogation theory, which outlines how to encourage readers to recall relevant background knowledge while reading text materials. The theory suggests that the strategy increases the likelihood that readers will integrate what they read with what they know to make new knowledge. The setting for the study more closely resembled classroom conditions compared to similar studies in the past. Unlike previous studies on reading comprehension, students read a challenging passage from the textbook used in a science course in which they were enrolled. In addition, the text was longer than that used in clinical research. The college students (n = 294) in this study were randomly assigned to either a questioning strategy treatment or a rereading placebo-control. While reading, treatment students were presented with statements taken from regular intervals in their textbook (about every 150 words) and asked a simple why question about each of these statements. Significant differences were found favoring elaborative interrogation theory and its question strategy treatment over the placebo-control in terms of science comprehension even after significant estimated predictors of prior knowledge and verbal ability were statistically controlled or accounted for by removing the statistical contributions of these predictors to the main effects. (Contains 5 tables and 1 figure.)