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Objective Early screening for autism spectrum disorder (ASD) is critical for timely intervention, making the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) a widely adopted tool globally. However, a recent systematic synthesis of its comparative accuracy is lacking. This review aimed to evaluate the screening accuracy of the M-CHAT-R/F against other ASD screening instruments.Design A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A narrative synthesis was employed to integrate findings across diverse study designs and methodological quality was assessed using the Joanna Briggs Institute checklist.Eligibility criteria Peer-reviewed, English-language observational studies published between January 2020 and October 2025 that compared the accuracy metrics of the M-CHAT-R/F with alternative screening tools.Information sources Scopus, PubMed, ScienceDirect and ProQuest.Results From 172 identified articles, six high-quality studies encompassing 12 633 participants aged 12–48 months were analysed. The synthesis revealed a complex performance profile for the M-CHAT-R/F. While its sensitivity for detecting potential cases was highly inconsistent, its negative predictive value remained consistently high, reliably identifying children who screened negative. Conversely, the tool demonstrated variable specificity and a persistently low positive predictive value, indicating a substantial false-positive burden and reduced confidence in positive results. Furthermore, the M-CHAT-R/F’s accuracy was highly age-dependent, with performance degrading outside the optimal 16–30-month window compared with other specialised tools.Conclusions The M-CHAT-R/F may not be an optimal instrument in every clinical setting. Its clinical utility may be limited by variable sensitivity and a lower positive predictive value, potentially creating a higher false-positive burden. Clinicians and health systems should consider adopting age-specific, tiered screening protocols to improve diagnostic efficiency and better allocate intervention resources.