OBJECTIVE: To understand the demographic, attitudinal, behavioral, and clinical characteristics of people who are likely to participate in clinical trials. METHODS: Analyses were based on a 12-page questionnaire mailed to U.S. adults in 2000. A total of 21,986 responses were received. Respondents were nationally representative based on gender, age, race, and geographic region; results were subsequently weighted and projected to the U.S. population. Participants were asked if they had ever participated in a clinical trial and whether they would ever consider participating in one. RESULTS: Among those who never participated in a clinical trial, 33% said they would strongly consider participating in the future. This group differed in some dramatic ways from the 26% who said they would definitely not consider participating in a clinical trial. For example, those who would participate were more likely to be female (55% v. 49%), younger (43 v. 47 years), and white (77% v. 70%). Behaviorally, likely participants were more likely to drink alcohol (64% v. 55%), smoke (27% v. 22%), visit physicians (4.0 v. 3.6 visits in six months), and use the internet for healthcare information (13% v. 6%). Attitudinally, those willing to participate were more likely to harbor alternative healthcare attitudes (e.g., “would try acupuncture” 38% v. 17%) and less likely to be satisfied with their current medical care (39% v. 47%). Clinically, they were more likely to be diagnosed with a range of comorbid medical conditions such as depression (15% v. 6%), migraines (16% v. 8%), and nasal allergies (32% v. 21%). CONCLUSION: People who are likely to participate in clinical trials look, think, and behave differently than those who are not likely to participate. Trail design and analysis should consider these differences and their possible impact on clinical, economic, and humanistic outcomes.