Informed consent documents are designed to convey the risks of medical procedures to patients, yet they are often difficult to understand; this is especially true for individuals with limited health literacy. An important opportunity for advancing knowledge about health literacy and informed consent involves examining the theoretical pathways that help to explain how health literacy relates to information processing when patients read consent forms. In this study, we proposed and tested a model that positioned self-efficacy as a mediator of the association between health literacy and patients' comprehension and assessment of informed consent documentation. Findings from structured interviews with patients (n = 254) indicated that lower health literacy predicted lower self-efficacy, which predicted feeling less well informed and less prepared, being more confused about the procedure and its hazards, and wanting more information about risks. Incorporating awareness of self-efficacy into disclosure documents and consent conversations may be a useful means of prompting patients to ask questions that can help them make informed decisions about care.