The present studies experimentally compared the effectiveness of self-explaining versus taking notes for improving comprehension of a difficult science among readers who varied in prior knowledge, reading skill, and later vocabulary skill. Study 1 (N = 70) examined how instructions to simply “note-take” or “self-explain” influenced text-based and inferential comprehension. Task did not influence comprehension performance but, as expected, readers with higher science prior knowledge outperformed their less knowledgeable peers, who also earned lower scores on inferential questions compared to text-based questions. To replicate and extend these findings, Study 2 (N = 60) provided readers with more specific, distinct instructions and examples for self-explanation and note-taking tasks prior to engaging in the same task. The results showed that, in the self-explanation task, high-knowledge readers outperformed low-knowledge readers on the text-based questions. These results suggest that self-explanation supported more knowledgeable and skilled readers for text-based questions.