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Background: The present randomized, double-masked, placebo-controlled, parallel-arm study examines the impact of adjunctive subantimicrobial-dose doxycycline (SDD) on the local inflammatory response through cytokine and chemokine levels in gingival crevicular fluid (GCF) samples from patients with chronic periodontitis., Methods: Forty-six patients with chronic periodontitis received scaling and root planing with or without adjunctive SDD. GCF samples were collected and clinical parameters including probing depth, clinical attachment level, gingival index, and plaque index were recorded every 3 months for 12 months. GCF tumor necrosis factor-α, interleukin (IL)-6, IL-4, IL-10, IL-13, IL-17, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, monocyte chemoattractant protein 1, and regulated on activated normal T-cell expressed and secreted protein levels were determined by xMAP multiplex immunoassay., Results: Significant improvements were observed in all clinical parameters in both groups over 12 months (P <0.0125), whereas the SDD group showed significantly better reduction in gingival index, probing depth, and gain in clinical attachment compared to the placebo group (P <0.05). Decrease in IL-6 in the SDD group was significantly higher compared to the placebo group at 6 and 9 months in deep pockets (P <0.05), whereas tumor necrosis factor-α was significantly reduced in moderately deep pockets (P <0.05). SDD resulted in a stable IL-4 and IL-10 response while reducing the monocyte chemoattractant protein 1 levels at 3 months (P <0.05)., Conclusions: These results show that SDD, as an adjunct to non-surgical periodontal therapy, stabilizes the inflammatory response by promoting the suppression of proinflammatory cytokines and increasing the anti-inflammatory cytokines. The chemokine activity would account for the regulation of the inflammatory response to SDD therapy.