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(1) Background: Clear orthodontic aligners support the development of oral biofilms, which could lead to interferences with the oral microbiota already existing and the deterioration of oral health, with the development of dental caries, periodontal disease and even systemic infections. Therefore, preventive oral health care requires a cleaning and disinfection procedure for aligners. (2) Methods: A systematic review of the literature was conducted across four databases following the PRISMA guidelines up to May 2021, combining an electronic and a manual search. Prospective studies, including randomized controlled trials (RCTs), crossover studies (COSs) and controlled clinical trials (CCTs), published in the English language without time restrictions, evaluating the efficacy of cleaning and disinfection protocols for clear orthodontic aligners by comparing them with a placebo or a negative control, were included. The article selection, data extraction and risk of bias assessment were performed by two independent blinded review authors. In case of disagreement, a third author was solicited throughout the selection process. (3) Results: Among the 221 articles screened in the search process, 4 studies were included in the review, all designed as crossover studies (single arm without randomization with the same sequence of different cleaning and disinfection protocols for each participant). Different cleaning and disinfection methods were studied such as mechanical methods (brushing with toothpaste or vibration), chemical methods/pharmaceutical products (chlorhexidine antibacterial substance, anionic or cationic detergents or effervescent tablets) or combinations of both. (4) Conclusion: Although the determination of the most remarkable method of cleaning and disinfection was impossible because no direct comparison was conducted between all these methods, a multi-step protocol, including the combination of a mechanical and a chemical method, seems to be the most effective approach. Further research is needed to define the most preventive oral health care protocol. Registration: PROSPERO CRD 42021278498.