Background: The U.S. health care system has been under immense scrutiny for ever-increasing costs and poor health outcomes for its patients. Comparative Effectiveness Research (CER) has emerged as a generally accepted practice by providers, policy makers, and scientists as an approach to identify the most clinical- and cost-effective interventions for treating patients. The objective of CER is to produce the scientific evidence that identifies the most effective approaches to deliver health care services, including: various clinical protocols, drugs, and/or medical devices. Recent investments in CER and health information technology (HIT or informatics) have served as catalysts for producing more electronic clinical data to conduct CER. Patient registries are one of the primary means to generate CER evidence using electronic clinical data; however, these data sources can be highly complex and unsustainable business models. Objective: This study will highlight four U.S.-based patient registry programs that utilize electronic clinical data and discuss how each has built a sustainable business model and addressed the informatics barriers unique to patient registries. The goal is to develop a conceptual framework that can be leveraged by other registry programs and highlight unique challenges that can be addressed by policy. Research Question: How can program administrators address informatics barriers to building observational comparative effectiveness research studies using electronic clinical data? Methods: The purpose of this multi-case study is to collect, synthesize and share lessons from four U.S.-based patient registries that have built data infrastructures using electronic clinical data for comparative effectiveness research. Using the Boone Framework, my evaluation is focused on challenges that fall into four primary domains, which are: (1) Standards; (2) Information governance; (3) Privacy & information security; and (4) Business model. The author will utilize an interview method to examine the key elements of each patient registry utilizing this framework to: (1) share key lessons learned with practitioners that are looking for build patient registries that utilize electronic clinical data, and (2) identify the public policy implications to building these programs. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]