The purpose of this experimental study is to investigate the effects of using content acquisition podcasts (CAPs), an example of instructional technology, to provide vocabulary instruction to adolescents with and without learning disabilities (LD). A total of 279 urban high school students, including 30 with LD in an area related to reading, were randomly assigned to one of four experimental conditions with instruction occurring at individual computer terminals over a 3-week period. Each of the four conditions contained different configurations of multimedia-based instruction and evidence-based vocabulary instruction. Dependent measures of vocabulary knowledge indicated that students with LD who received vocabulary instruction using CAPs through an explicit instructional methodology and the keyword mnemonic strategy significantly outperformed other students with LD who were taught using the same content, but with multimedia instruction that did not adhere to a specific theoretical design framework. Results for general education students mirrored those for students with LD. Students also completed a satisfaction measure following instruction with multimedia and expressed overall agreement that CAPs are useful for learning vocabulary terms.