Underrepresentation of HIV-infected Hispanics and African Americans in clinical trials seriously limits our understanding of the benefits and risks of treatment in these populations. This qualitative study examined factors that racial/ethnic minority patients consider when making decisions regarding research participation. A total of 35 HIV-infected Hispanic and African American patients enrolled in clinical research protocols at the National Institutes of Health were recruited to participate in focus groups and in-depth interviews. The sample included mostly male participants (n = 22), had a mean age of 45, had nearly equal representation of race/ethnicity, and were diagnosed 2 to 22 years earlier. Baseline questionnaires included demographics and measures of social support and acculturation. Interviewers had similar racial/ethnic, cultural, and linguistic backgrounds as the participants. Four major themes related to the decisions of participants to enroll in clinical trials emerged, which are as follows: enhancers, barriers, beliefs, and psychosocial context. Results may help researchers develop strategies to facilitate inclusion of HIV-infected Hispanics and African Americans into clinical trials.