PURPOSE: Cohort studies investigating genes, environment, and lifestyle require large study populations. To recruit and retain participants, it is important to understand the relative significance of influences on people's motivation to participate. To this end, 4659 Americans were surveyed about support for and willingness to participate in a proposed large cohort study. METHODS: An online survey of US adults was conducted between December 2007 and January 2008. To measure the influence of study burden, compensation and receipt of individual research results on willingness to participate, respondents were randomized to one of eight different study scenarios. RESULTS: Most respondents (84%) supported the study, and 60% would participate. Returning research results (odds ratio = 1.6, 95% confidence interval 1.3-1.8) and increasing compensation from $50 to $200 (odds ratio = 1.5, 95% confidence interval 1.2-1.7) were associated with increased willingness to participate. Decreasing study burden was less important (odds ratio = 1.2, 95% confidence interval 1.0-1.4). Three in four respondents would be less likely to participate without the return of research results. Support and willingness varied little among demographic groups; variation in influences of the three factors on willingness was observed. CONCLUSION: Widespread support exists in the general public for a large national cohort study. Providing individual research results is a strong motivation to participate; compensating participants $200 may increase participation a similar amount. Incentives, recruitment, and return of results could be tailored to demographics groups' interests.