Objectives: We conducted this study to evaluate and compare the efficacy of azithromycin treatment as an adjunctive therapy to oral hygiene measures in reducing drug-induced gingival hyperplasia in renal transplant patients under cyclosporine and those under tacrolimus therapy. Material & Methods: Patients diagnosed with early to moderate gingival overgrowth with stable allograft function were included in the study. These patients had been taking either cyclosporine or tacrolimus for more than 6 months. The patients were randomized equally into three groups. Two groups had received 500-mg azithromycin for 5-days given at baseline only. While the control group received placebo in addition to the oral hygiene program .The clinical periodontal parameters were assessed and included the plaque index, bleeding on probing index, the gingival overgrowth index, and the probing depth. They were evaluated at the baseline and at flow up time (1, 3, 6 months). Results: Seventy five kidney transplant recipients (48 men, 27 women) were included in this study. At the baseline time all groups were similar in the clinical parameters with no statistically significant difference (P>.05). At follow up time intervals all groups showed improvement over baseline measurements however both groups who received azithromycin showed more favorable results manifested by reduction of gingival bleeding and the depth of gingival sulcus. However, this improvement was more in the cyclosporine group than the tacrolimus group and the difference was statistically significant (P >.05). Conclusions: Azithromycin is an effective therapeutic tool in the management of drug-induced gingival overgrowth as it is conservative, well tolerated, and rapidly effective with minimal side effects; especially in renal transplant patients under cyclosporine therapy.