Overall, the clinical evidence regarding the use of clinical decision support systems for appropriate medical imaging is mixed. Evidence from two randomized controlled trials that supported the clinical benefit and safety of clinical decision support systems for appropriate medical imaging. Together the confidence in these findings is mixed as one randomized controlled trial presented evidence of attrition bias in addition to other methodological quality concerns. Low-quality evidence from 3 of 14 before and after studies was also identified that reported increased diagnostic yield along with no increased adverse events, however mixed evidence of clinical efficacy for clinical decision support systems was also reported in the low-quality evidence. Findings of the before and after studies were limited by a study design that failed to control for potential temporal effects unrelated to the intervention. None of the identified evidence reported statistically significant decreases in diagnostic yield, increases in inappropriate imaging, or increases in adverse events that followed implementation of clinical decision support systems for appropriate medical imaging. Additional high-quality evidence of clinical benefit and safety of clinical decisions support systems for appropriate medical imaging would increase the confidence in the evidence identified in this report. Ideally, future studies would provide sufficient intervention information for replication and aim to identify factors that lead to a successful implementation of clinical decision support systems. No evidence of the cost-effectiveness of clinical decision support systems for appropriate imaging was identified.