Introduction: Health information generated by health care encounters, research enterprises, and public health is increasingly interoperable and shareable across uses and users. This paper examines the US public’s willingness to be a part of multi-user health information networks and identifies factors associated with that willingness. Methods: Using a probability-based sample (n = 890), we examined the univariable and multivariable relationships between willingness to participate in health information networks and demographic factors, trust, altruism, beliefs about the public’s ethical obligation to participate in research, privacy, medical deception, and policy and governance using linear regression modeling. Results: Willingness to be a part of a multi-user network that includes health care providers, mental health, social services, research, or quality improvement is low (26 percent–7.4 percent, depending on the user). Using stepwise regression, we identified a model that explained 42.6 percent of the variability in willingness to participate and included nine statistically significant factors associated with the outcome: Trust in the health system, confidence in policy, the belief that people have an obligation to participate in research, the belief that health researchers are accountable for conducting ethical research, the desire to give permission, education, concerns about insurance, privacy, and preference for notification. Discussion: Our results suggest willingness to be a part of multi-user data networks is low, but that attention to governance may increase willingness. Building trust to enable acceptance of multi-use data networks will require a commitment to aligning data access practices with the expectations of the people whose data is being used.