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We assessed disagreements between nonrandomized controlled studies based on real-world data (NRCS-RWDs) and randomized controlled trials (RCTs). We systematically searched for studies that compared treatment effect estimates from NRCS-RWDs and RCTs on the same clinical question. We assessed the potential difference between NRCS-RWDs and RCTs related to internal and external validity. We calculated various meta-epidemiological measures to assess agreement. In case of disagreements, we tried to identify the probable cause