Background: Host modulation therapy represents a treatment concept in which drug therapies are applied as an adjunctive therapy to conventional periodontal treatments to counteract the destructive effects of the host inflammatory response. Methods: This is a randomized split-mouth clinical trial in which a total of 40 outpatients diagnosed with mild-moderate chronic periodontitis with at least two pairs of contralateral anatomically matching proximal tooth surfaces showing probing depth of ≥ 5 mm were enrolled. Full-mouth scaling and root planing (SRP) was performed for all patients and pockets larger than 5 mm were selected for application of the studied gels. The selected sites were randomly divided into group A (piroxicam + metronidazole) and group B (piroxicam). Recall appointments were scheduled every two weeks within 3 months. The periodontal parameters, assessed in the molar teeth, also recorded that changes in clinical parameters during the study. Results: A total of 34 patients, with mean age of 45. 2± 8. 6 (range 32-60) years, none of whom developed unpleasant side effect, were enrolled. Plaque index was significantly higher in group A; further it was a statistically significant difference in Bleeding on probing levels in group A at the baseline to last interval recall while current study. The results exhibited significant reductions in pocket depth within 3 months when compared to the baseline values, while the combination adjunctive therapy was more effective to reduce pocket depth. Furthermore, both groups showed a statistically significant mean reduction in clinical attachment level (CAL), but in the test group A had a higher CAL gain than in the control group B (P=0. 039). Conclusions: The use of a combination of drugs can help reduce the clinical signs of periodontal disease, therefore, by changing the patient’ s health habits along with periodontal treatment, the mechanical treatment that a microbial plaque can be obtained, and then the use of piroxicam + metronidazole gel as a complementary therapy, the recovery process can be accelerated.