Background: Along with conventional surgical therapy, systemic antibiotics may provide more effective treatment in smokers by targeting tissue-invasive bacteria. The aim of this randomized, placebo-controlled, double-masked clinical trial was to evaluate the adjunctive effects of systemic azithromycin (AZM) in combination with periodontal pocket reduction surgery in the treatment of chronic periodontitis in smokers., Methods: Thirty patients with a greater than one pack/day smoking habit and generalized moderate to severe chronic periodontitis were randomized to the test (surgery plus 3 days of AZM, 500 mg) or control group (surgery plus 3 days of placebo). Full-mouth probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), plaque index, and wound healing indices (WHI) were assessed at baseline and at 2 weeks and 1, 3, and 6 months following surgical intervention. Plaque and gingival crevicular fluid were collected for trypsin-like enzyme activity (benzoyl-dl-arginine naphthylamine) and bone biomarker (crosslinked telopeptide of type I collagen [ICTP]) analyses, respectively, at baseline, 2 weeks, and 1, 3, and 6 months., Results: Surgical treatment of moderate (PD = 4 to 6 mm) and deep (PD > 6 mm) pockets significantly improved clinical parameters of treated and untreated teeth (CAL gain, PD reduction, and reduction of BOP). The additional use of AZM did not enhance this improvement nor did it promote reduction of ICTP levels. Compared to the control group, the test group had significantly better WHI scores at 1 month, significantly less GI at 2 weeks, and sustained reductions of red-complex bacteria with trypsin-like enzyme activity at 3 months. For non-surgery teeth, only the test group showed significant gains in overall CAL compared to baseline., Conclusions: The findings of this pilot study demonstrated that in heavy smokers, adjunctive systemic AZM in combination with pocket reduction surgery did not significantly enhance PD reduction or CAL gain. However, the clinical value of adjunctive AZM may be appreciated by more rapid wound healing, less short-term gingival inflammation, and sustained reductions of periopathogenic bacteria. More expanded studies are recommended to better determine the clinical effects of adjunctive AZM in patients who smoke.