Aim We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury. Material and Methods 60 rats were randomly assigned to 6 groups (n=10) and ligatures were placed around lower first molars of three groups. The other three groups were used as negative controls. Ligatures were removed after 10 days of periodontitis induction and all groups were submitted to treatment with aspirin (Asp) (30 mg/kg), clopidogrel (Clop) (75 mg/kg) or NaCl 0.9% intragastrically once daily for 3 days. Periodontal tissue was assessed by the measurement of CXCL12, CXCL4, CCL5 and PDGF by ELISA; histomorphometric analysis of PMN infiltration, attachment loss, bone loss and osteoclast numbers and quantification of blood vessels by imunnohistochemistry. Results During periodontal repair and treatment with NaCl 0.9%, CCL5 was decreased and CXCL12 increased when compared to negative control groups. Asp and Clop did not affect CCL5 expression, decreased CXCL12 but only Clop decreased CXCL4 and PDGF content compared to saline-treated animals. Clop increased blood vessel number, reduced PMN count, and decreased attachment and bone loss, also decreased osteoclast number in animals submitted or not to periodontal repair. Conclusion Systemic administration of Clop during 3 days improved the repair process associated with experimental periodontal disease, suggesting that it may have therapeutic value under situations where tissues undergo a transition from inflammation to repair.