In this limited PCORI Funding Announcement (PFA) for Clinical Research Networks (CRNs) and Health Plan Research Networks (HPRNs), PCORI seeks applications for high-quality clinical studies to answer important patient- and stakeholder-prioritized clinical comparative effectiveness research (CER) questions that remain unanswered due to insufficient or inconclusive evidence. An important aim of this PFA is to promote PCORnet sustainability through collaboration and engagement with non-PCORI co-funders in the conduct of CER and to promote greater completeness of PCORnet data through linkages of CRN electronic data with that of health plans, disease registries, and other complementary data sources on individuals within CRN or HPRN databases. These capabilities—attracting external funders and improving PCORnet’s capacity for data linkage—are fundamental steps in building a sustainable national research infrastructure that attracts a diverse set of public and private funders of research.