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Objectives: A systematic review and meta-analysis were performed to answer this research question: "Does combined in-office (IO) and at-home (AH) bleaching produce improved color change and lower tooth sensitivity (TS) better than solely AH or IO bleaching in adults?", Material and Methods: Randomized controlled trials in adults that compared combined versus sole application bleaching were included. The risk of bias (RoB) was evaluated using the Cochrane Collaboration tool. Meta-analyses were conducted for color change in shade guide units (∆SGU) and with a spectrophotometer (∆E*), risk, and intensity of TS, using the random effects model. Heterogeneity was assessed with Cochran's Q test and I 2 statistics. GRADE assessed the quality of the evidence. PubMed, Scopus, Web of Science, LILACS, BBO, Cochrane Library, SIGLE, IADR abstracts, unpublished, ongoing trial registries, dissertations, and theses were searched on August 28, 2017 (updated on January 29, 2019)., Results: Twelve studies remained. Two were considered to have low RoB. For combined vs. IO bleaching, no significant difference for ∆E*, ∆SGU, and risk of TS were observed; data were not available to analyze the intensity of TS. For combined vs. AH bleaching, no significant difference for ∆E*, ∆SGU, but lower TS to risk (RR 1.40, 95% 1.10 to 1.80) and intensity (MD 1.40, 95% CI 0.18 to 2.63) were detected for AH bleaching. Quality of evidence was graded as low or very low in all meta-analyses., Conclusion: Lower risk and intensity of TS was observed for the solely AH group without jeopardizing color change. However, more studies are still encouraged due to the low quality of evidence for most of the outcomes., Clinical Relevance: If clinicians are to choose between combined or sole AH bleaching, the solely AH may be preferable; combined bleaching may potentiate the risk of TS without benefits in color change. For combined or sole IO bleaching, no important clinical difference in color change and risk of TS were detected; however, intensity of TS could not be compared due to lack of data. Further studies should be conducted due to the low/very low quality of the evidence.