Background <p>Patients often have suboptimal understanding of informed consent in clinical trials, impeding their ability to make informed decisions about participation. Additionally, translating complex informed consent information from English into other languages can introduce new areas of misunderstanding for patients. This qualitative study examined how English- and Spanish-speakers understood and perceived a complex clinical informed consent form.</p> Methods <p>We tested an informed consent form for a clinical trial on a gynecological medication with women who represented the study population. We conducted 18 semi-structured interviews with English- (<i>n</i> = 9) and Spanish-speaking (<i>n</i> = 9) participants to explore areas of misunderstanding, concerns, and preferences. With Spanish-speakers, we tested two professionally translated versions of the informed consent form—one generated by general translators and the second by translators with medical and scientific expertise. We used thematic analysis to explore patterns in the data.</p> Results <p>Five themes were common across both English- and Spanish-speakers: difficulty with medical jargon; unfamiliarity with the drug development and testing process; desire for understandable numeric information; aversion to uncertain or conflicting evidence; and affective reactions to information. Spanish-speakers generally preferred language from the medical translation over the general version, though this preference was not consistent.</p> Conclusions <p>Findings underscore the importance of pretesting informed consent materials to ensure that they are understandable, avoid difficult language, and do not evoke negative emotions or reactions, particularly when communicating about risk and uncertainty. Findings also suggest using a combination of translation approaches, when resources allow, and reinforce the value of using plain language familiar to audiences.</p>