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Summary Objective To assess the effect of clear aligners on the speech of patients undergoing orthodontic therapy through a systematic review of the literature. Search methods and selection criteria: The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) CRD42021278694. An electronic search of the Scopus, Embase, Pubmed, and Web of Science databases was done for papers published between January 2000 till September 2021. Studies that evaluated speech difficulties in patients undergoing orthodontic treatment with clear aligners using objective and subjective analyses were included. The evaluated primary outcome was speech difficulties. Secondary outcomes were time to adaptation and recovery from speech difficulties. Study quality was assessed based on the Cochrane Handbook for Systematic Reviews of Interventions Handbook guidelines and ROBINS-I tool. Results Two hundred and eighty-three articles were screened to identify seven studies (n = 332 patients) that assessed speech difficulty with aligners, of which two were randomized trials. Meta-analysis was not performed due to the heterogeneity in the study designs. Five studies compared speech difficulty with aligners to fixed appliances. Two studies showed a moderate risk of bias and five studies had a serious risk of bias. Level of evidence was downgraded to low due to the methodological insufficiencies and risk of bias in the studies. All seven studies reported that aligners could influence the clarity and delivery of speech, similar to fixed appliances. Various phonemes were affected including /s/,/z/,/zh/,/sh/,/th/,/ch/ on wearing aligners. Errors in articulation of consonants and sibilants were noted with lisping and speech impairment. These speech difficulties were temporary and most patients recovered in 7–14 days while few patients took 30-60 days to recover. Conclusion The likelihood of speech difficulties appears high with clear aligners. However, patients adapt quickly and speech returns to normal. The results of this review must be interpreted with caution and more well-designed randomized trials examining long-term effects of aligners on speech are indicated. Clinical Significance Orthodontists should counsel patients opting for clear aligner treatment of the potential transient speech difficulties. Registration The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) CRD42021278694.