The present study evaluated the effects of systemic minocycline on clinical and biochemical parameters of chronic periodontitis, which is a common inflammatory disorder of the periodontium initiated by the presence of bacteria in the gingival sulcus. Besides nonsurgical periodontal therapy, 20 individuals received minocycline systemically while another 20 subjects received placebo capsules for 2 weeks. Plaque index (PI), sulcus bleeding index (SBI), probing depth (PD), and relative attachment level (RAL) were measured and gingival crevicular fluid (GCF) samples were obtained at baseline and first, third, and sixth months. Matrix metalloproteinase-8 (MMP-8) and prostaglandin E-2 (PGE(2)) levels were analyzed by enzyme immunoassay method. Significant improvements in all parameters in both groups were recorded. In the minocycline group, changes in PI and SBI were significantly greater only at first month, whereas reductions in PD, RAL, MMP-8, and PGE(2) levels were greater at all times. MMP-8 and PGE(2) exhibited positive correlations with SBI, PD, and each other. Minocycline demonstrated clinical benefit for periodontal therapy and provided further improvements on inflammatory mediators promising a host-modulating capacity.