Registry-based randomized controlled trials (RRCTs) are increasingly used, promising to address challenges associated with traditional randomized controlled trials. We identified strengths and limitations reported in planned and completed RRCTs to inform future RRCTs. We conducted an environmental scan of literature discussing conceptual or methodological strengths and limitations of using registries for trial design and conduct (n = 12), followed by an analysis of RRCT protocols (n = 13) and reports (n = 77) identified from a scoping review. Using framework analysis, we developed and refined a conceptual framework of RRCT-specific strengths and limitations. We mapped and interpreted strengths and limitations discussed by authors of RRCT articles using framework codes and quantified the frequencies at which these were mentioned. Our conceptual framework identified six main RRCT strengths and four main RRCT limitations. Considering implications for RRCT conduct and design, we formulated ten recommendations for registry designers, administrators, and trialists planning future RRCTs. Consideration and application of empirically underpinned recommendations for future registry design and trial conduct may help trialists utilize registries and RRCTs to their full potential.