Introduction: The treatment of periodontal disease can consist of bacterial plaque reduction, risk factor elimination, and metalloproteinase inhibitor medication. The level of matrix metalloproteinases (MMPs) are regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs) as well as therapeutic low-dose doxycycline. The aim of the study was to evaluate the effect of the initial phase of periodontal treatment and the effect of doxycycline on clinical parameters and the MMP-8, MMP-9, and TIMP-1 concentrations in the saliva and peripheral blood of patients with chronic periodontitis. Materials and Methods: The study group consisted of 33 patients with chronic periodontitis. Conventional periodontal treatment (scaling and root planing) was conducted on all the patients and doxycycline (20 mg orally) was administered twice daily for three months. Thirty-three controls received the conventional treatment only. Clinical scores (PI, BI, PD, CAL) were recorded before and three months after the treatment. MMP-8, MMP-9, and TIMP-1 concentrations in saliva and peripheral blood were measured by ELISA before and after the treatment of 20 patients from the study group and 13 of the controls.Results: The application of doxycycline 20 mg resulted in significant improvement in clinical parameters compared with the conventional periodontal treatment. Doxycycline did not produce significant reductions in MMP-8 and MMP-9 levels in saliva observed after the conventional treatment. The study revealed increases in the TIMP-1 concentration and the MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios in saliva and blood after treatment with doxycycline. Conclusions: The study confirmed the modulating effect of doxycycline on the host response in chronic periodontitis.