Given the potential of health internet-registers, this study examined how such registers can be made more effective and efficient. This involved investigating the actual barriers to usage experienced by those for whom such registers are established to help. To elicit responses regarding the opinions, views, and experiences of participants, concerning their various reasons for non-progression or non-completion of the pilot UK MS Register, a list of ten potential key areas of difficulty, in the form of short statements, was e-mailed to participants. A content analysis revealed that there were four main areas of concern that could represent potential barriers for health internet-registers, in general, and that need to be considered when establishing, designing, and developing such registers: technical aspects of using the internet; computer literacy and ability, encompassing website design, clarity, and user-friendliness; symptom mismatches with register content; and condition-specific effects and impacts as barriers to internet-register use.