BACKGROUND: The goal of restoring caries lesions is to protect the pulp, prevent progression of the disease process, and restore the form and function of the tooth. The purpose of this systematic review was to determine the effect of different direct restorative materials for treating cavitated caries lesions on anterior and posterior primary and permanent teeth. TYPE OF STUDIES REVIEWED: The authors included parallel and split-mouth randomized controlled trials comparing the effectiveness of direct restorative materials commercially available in the United States placed in vital, nonendodontically treated primary and permanent teeth. Pairs of reviewers independently conducted study selection, data extraction, and assessments of risk of bias and certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. The authors conducted pair-wise meta-analyses to summarize the evidence and calculated measures of association and their 95% CIs. RESULTS: Thirty-eight randomized controlled trials were eligible for analysis, which included data on Class I and Class II restorations on primary teeth and Class I, Class II, Class III, Class V, and root surface restorations on permanent teeth. Included studies assessed the effect of amalgam, resin composite, compomer, conventional glass ionomer cement, resin-modified glass isomer cement, and preformed metal crowns. Moderate to very low certainty evidence suggested varying levels of effectiveness across restorative materials. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Owing to a relatively low event rate across various outcomes indicating restoration failure, there was limited evidence to support important differences between direct restorative materials used in practice.