OBJECTIVES: To evaluate the efficacy of subgingival instrumentation (PICOS-1), sonic/ultrasonic/hand instruments (PICOS-2) and different subgingival instrumentation delivery protocols (PICOS-3) to treat periodontitis. METHODS: Systematic electronic search (CENTRAL/MEDLINE/EMBASE/SCOPUS/LILACS) to March 2019 was conducted to identify randomized controlled trials (RCT) reporting on subgingival instrumentation. Duplicate screening and data extraction were performed to formulate evidence tables and meta-analysis as appropriate. RESULTS: As only one RCT addressed the efficacy of subgingival instrumentation compared to supragingival cleaning alone (PICOS-1), baseline and final measures from 11 studies were considered. The weighted pocket depth (PD) reduction was 1.7 mm (95%CI: 1.3-2.1) at 6/8 months and the proportion of pocket closure was estimated at 74% (95%CI: 64-85). Six RCTs compared hand and sonic/ultrasonic instruments for subgingival instrumentation (PICOS-2). No significant differences were observed between groups by follow-up time point or category of initial PD. Thirteen RCTs evaluated quadrant-wise vs full-mouth approaches (PICOS-3). No significant differences were observed between groups irrespective of time-points or initial PD. Five studies reported patient-reported outcomes, reporting no differences between groups. CONCLUSIONS: Nonsurgical periodontal therapy by mechanical subgingival instrumentation is an efficacious means to achieve infection control in periodontitis patients irrespective of the type of instrument or mode of delivery. Prospero ID:CRD42019124887