Background: Along with conventional periodontal surgical therapy, local delivery of antibiotics may provide more effective treatment in smokers by targeting tissue-invasive bacteria. The aim of this randomized, clinical trial was to evaluate the adjunctive effects of subgingivally delivered 0.5% azithromycin (AZM) as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis in smokers versus non smokers. Methods: 38 sites in patients of chronic periodontitis were randomized and categorized into two treatment groups: Group 1 consisted of 19 sites in patients who were smokers and Group 2 consisted of 19 sites in non smokers, who received Scaling and Root Planing (SRP) plus 0.5% azithromycin gel Local drug delivery. Clinical parameters were recorded at baseline, 1 and 2 months. They included probing depth (PD) and clinical attachment level (CAL) and percentage bone fill. Results: Azithromycin resulted in significant improvements in both the groups. Mean decrease in PD in non smokers by the end of 2 months was 3.903mm and in smokers was 3.917mm. Gain in CAL in non smokers by the end of 2 months was 3.879mm and in smokers it was 3.920mm. Mean bone fill at one month for smokers was 15.86% and was 26.58% at 2 months. In non-smokers the mean bone fill was 17.19% at 1 month and 24.03% at 2 months. Conclusions: When compared to the non smokers, the adjunctive use of 0.5% AZM resulted in similar improvement in clinical outcome in the treatment of chronic periodontitis among smokers. Local drug delivery of Azithromycin gel contributed to decrease in probing pocket depth, gain in clinical attachment level and in alveolar bone. The apparent bone regeneration also raises the intriguing possibility that Azithromycin encourages bone formation once tissue inflammation has subsided.