INTRODUCTION: Patient-specific guides (PSGs) provide customized solutions and enhanced precision. However, the question remains: does clinical evidence support the added value of PSGs? This study critically appraises, summarizes, and compares the literature to assess the clinical value of PSGs in orthopedic surgery. MATERIALS AND METHODS: PubMed and Embase were used to search for studies reporting on randomized controlled trials (RCTs) that compared the use of PSGs with a control group for an orthopedic intervention, excluding knee arthroplasty. The risk of bias was assessed using the Cochrane risk-of-bias tool (RoB 2). The clinical value was expressed as patient reported outcome measures (PROMs), complications, accuracy, surgery duration, blood loss, and radiation exposure. Relative and absolute differences were determined, and whether these were negative or positive for using PSGs. RESULTS: From 6310 studies, 27 RCTs were included, covering various interventions. The studies' heterogeneity prevented meta-analysis. Six (22.2%) of the included articles scored low risk of bias. Significant differences in the benefit of PSGs were reported across all included metrics: 32.2% in PROMs, 22.7% in complications, 69.8% in accuracy, 42.1% in surgery duration, 46.7% in blood loss, and 93.3% in radiation exposure. No significant negative differences were found in any of the studies. CONCLUSION: PSGs generally show superior outcomes for accuracy and radiation exposure across multiple intervention types, while the reduction in complications was primarily significant in spinal fusion surgery. For PROMs, complications in other treatments, surgery duration, and blood loss, there may be clinical added value but future well-designed RCTs are needed to provide stronger evidence.