Context: Clinicians and treatment guideline developers are faced with a dilemma when the results of a new, large, well-conducted randomized controlled trial (RCT) are in direct conflict with the results of a previous systematic review (SR) and meta-analysis (MA).

Objective: To explore and discuss possible reasons for disagreement in results from SRs/MAs and RCTs and to provide guidance to clinicians and guideline developers for making well-informed treatment decisions and recommendations in the face of conflicting data.

Evidence acquisition: The advantages and limitations of RCTs and SRs/MAs are reviewed. Two practical examples that have a direct bearing on European Association of Urology guidelines on treatment recommendations are discussed in detail to illustrate the points to be considered when conflicts exist between the results of large RCTs and SRs/MAs.

Evidence synthesis: RCTs are the gold standard for providing evidence of the effectiveness of interventions. However, concerns regarding the internal and external validity of an RCT may limit its applicability to clinical practice. SRs/MAs synthesize all evidence related to a given research question, but two urologic examples show that the validity of the results depends on the quality of the individual studies, the clinical and methodological heterogeneity of the studies, and publication bias.

Conclusions: Although SRs/MAs can provide a higher level of evidence than RCTs, the quality of the evidence from both RCTs and SRs/MAs should be investigated when their results conflict to determine which source provides the better evidence. Guideline developers should have a well-defined and robust process to assess the evidence from MAs and RCTs when such conflicts exist.

Patient summary: We discuss the advantages and limitations of using data from randomized controlled trials and systematic reviews/meta-analyses in informing clinical practice when there are conflicting results. We provide guidance on how such conflicts should be dealt with by guideline organizations.