Background: Direct entry of personal health survey information into a computer by patients could streamline clinical data collection, improve completeness and accuracy of health information available to providers, and provide data for tailoring health education messages. Few computerized programs, however, have been developed to adapt the interface to diverse literacy levels, language, computer skills, and health literacy levels of the broad spectrum of patient populations. Methods: To develop such a program, we conducted cognitive response interviews with a diverse sample of 21 adult participants from two North Carolina health clinics. Participants were placed into one of three interview categories: (1) low reading skill level, low computer skills; (2) high reading skill level, low computer skills; and (3) high reading skill level, high computer skills. The 'think-aloud' technique was employed to elicit feedback on a series of computer interface screens and health risk assessment questions.Results: Interface-related findings showed that preference for touchscreen versus keyboard data entry was not strongly related to computer skill level but was related to question type. Respondents with limited education indicated that they would not click on a 'help' or hyperlink option to get more information and that frequent reminders of directions on the screen were needed. Content-related findings showed numerous misperceptions regarding meanings of common health questions and terminology (e.g., seat belt use and intravenous drugs). Conclusions: These findings have implications for health literacy and may have an impact on the accuracy of information obtained. Study results will be incorporated into the development and testing of an innovative, adaptive multimedia program.