Background: Mechanical plaque removal has been commonly accepted to be the basis for periodontal treatment. This study aims to compare the effectiveness of ultrasonic and manual subgingival scaling at different initial probing pocket depths (PPD) in periodontal treatment. Methods: English-language databases (PubMed, Cochrane Central Register of Controlled Trials, EMBASE, Medline, and ClinicalTrials.gov, by January, 2019) were searched. Weighted mean differences in primary outcomes, PPD and clinical attachment loss (CAL) reduction, were estimated by random effects model. Secondary outcomes, bleeding on probing (BOP), gingival recession (GR), and post-scaling residual dental calculus, were analyzed by comparing the results of each study. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. The GRADE approach was used to assess quality of evidence.