Summary Background The use of orthodontic aligners to treat a variety of malocclusions has seen considerable increase in the last years, yet evidence about their efficacy and adverse effects relative to conventional fixed orthodontic appliances remains unclear. Objective This systematic review assesses the efficacy of aligners and fixed appliances for comprehensive orthodontic treatment. Search methods Eight databases were searched without limitations in April 2019. Selection criteria Randomized or matched non-randomized studies. Data collection and analysis Study selection, data extraction, and risk of bias assessment was done independently in triplicate. Random-effects meta-analyses of mean differences (MDs) or relative risks (RRs) with their 95% confidence intervals (CIs) were conducted, followed by sensitivity analyses, and the GRADE analysis of the evidence quality. Results A total of 11 studies (4 randomized/7 non-randomized) were included comparing aligners with braces (887 patients; mean age 28.0 years; 33% male). Moderate quality evidence indicated that treatment with orthodontic aligners is associated with worse occlusal outcome with the American Board of Orthodontics Objective Grading System (3 studies; MD = 9.9; 95% CI = 3.6–16.2) and more patients with unacceptable results (3 studies; RR = 1.6; 95% CI = 1.2–2.0). No significant differences were seen for treatment duration. The main limitations of existing evidence pertained to risk of bias, inconsistency, and imprecision of included studies. Conclusions Orthodontic treatment with aligners is associated with worse treatment outcome compared to fixed appliances in adult patients. Current evidence does not support the clinical use of aligners as a treatment modality that is equally effective to the gold standard of braces. Registration PROSPERO (CRD42019131589).