OBJECTIVES: The aim of this scoping literature review was to report the findings of studies that have attempted to quantify external validity by comparing the patient population included in randomized controlled trials (RCTs) with patients from everyday clinical practice. METHODS: We conducted a literature review of English language journal articles published since 2003 that compared a RCT patient population with a ‘real-life’ patient population. Studies were limited to pharmaceutical interventions undertaken in adults. A protocol was developed that outlined the search approach. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double abstract review and data extraction were performed in line with protocol specifications. RESULTS: Out of 5456 de-duplicated abstracts, there were 73 studies that met the inclusion criteria. Studies covered a range of therapy areas, with the majority undertaken in mental health (n=18), cardiology (n=16), and oncology (n=13). Studies either assessed the proportion of people from a clinical setting that would be eligible for an RCT or undertook a post-hoc analysis of RCT patient characteristics compared with the real-world population. A range of comparisons were made, including demographic, socioeconomic, and clinical parameters. The vast majority of studies (n=59) concluded that study selection criteria excluded many patients from clinical practice; most commented on how this limited the RCT’s external validity. A number of recommendations were made to improve the generalizability of RCTs or facilitate better understanding of their limitations.  CONCLUSIONS:  RCTs designed to maximize internal validity frequently result in a loss of external validity.  Designers of RCTs should carefully weigh inclusion/exclusion criteria to ensure study objectives are met without unnecessarily sacrificing external validity, and the extent to which generalizability is compromised should be reported. Ultimately, a combination of explanatory and pragmatic studies is necessary to meet the diverse needs of regulators, prescribers, payers, and patients.