The aim of this systematic review is to evaluate whether use of local or systemic antimicrobials would improve clinical results of non-surgical periodontal therapy for smokers with chronic periodontitis (CP).Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and The Cochrane Central Register of Controlled Trials were searched up to and including March 2016. Randomized clinical trials of duration of at least 6 months were included if they reported on treatment of smokers (≥10 cigarettes per day for minimum 12 months) with CP with non-surgical periodontal therapy either alone or associated with local or systemic antimicrobials. Random-effects meta-analyses were undertaken to evaluate mean differences in probing depth (PD) and clinical attachment level (CAL).Of 108 potentially eligible articles, seven were included. Most individual studies (75%) testing locally delivered antibiotics reported that smokers benefited from this treatment approach. Pooled estimates found additional PD reduction of 0.81 mm (P = 0.01) and CAL gain of 0.91 mm (P = 0.01) at sites with baseline PD ≥5 mm. Conversely, meta-analysis on systemic use of antimicrobials failed to detect significant differences in mean changes from baseline, and only one trial supported their use.In smokers with CP, adjunctive use of local antimicrobials improved efficacy of non-surgical periodontal therapy in reducing PD and improving CAL at sites presenting PD ≥5 mm before treatment. Current evidence does not demonstrate similar gains when scaling and root planing plus systemic antimicrobial/antibiotics were associated with therapy.