Background Leucine-rich alpha-2 glycoprotein (LRG) is a novel acute phase protein involved in inflammation-associated diseases and that considered to be induced by multiple proinflammatory cytokines. This study aimed to investigate gingival crevicular fluid (GCF) and serum levels of LRG, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in patients with stage 3 periodontitis before and after non-surgical periodontal treatment.,Methods Twenty-five stage 3 periodontitis and twenty-five periodontally healthy individuals were enrolled in the study. Clinical periodontal measurements were recorded; periodontitis patients received non-surgical periodontal treatment, and GCF and serum samples were obtained at baseline and at 6 weeks after treatment. LRG, IL-6 and TNF-alpha were determined by ELISA.,Results GCF and serum LRG, IL-6 and TNF-alpha were significantly higher in periodontitis group than healthy controls (P < .001). A significant decrease in GCF and serum LRG, IL-6 and TNF-alpha was detected after periodontal treatment compared with baseline values of periodontitis patients (P < .001).,Conclusion Our findings revealed that LRG expression was increased in stage three periodontitis both locally and systemically, and non-surgical periodontal therapy was effective in reducing LRG levels in GCF and serum of these patients.