The enrolling of adequate participants into HIV experimental drug trials presents an important challenge. We systematically reviewed the literature to identify barriers and concerns amongst HIV patients to participation in HIV clinical drug trials. We reviewed studies for validity and content, and generated pooled estimates of the frequency with which patients identified particular issues by pooling across studies that presented results as proportions. We included three semi-structured interview studies, two open-ended questionnaires, and nine quantitative studies. Major barriers to participation included fear of side-effects, distrust of researchers, general concerns about research design, interference in everyday life or changes in routine, and social discrimination. Results from the quantitative studies indicated that the most prevalent barriers were as follows: suspicions about the drug itself (53%, 95% CI 24-83%), patients were not informed or believed they were not eligible (38%, 25-50%), and travel or transport obstacles (39%, 21-57%). The findings of this study should aid drug trialists in developing strategies to maximise participation and cooperation in HIV clinical drug trials while adequately informing and protecting prospective participants.