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Background and Objective: There have been few studies of gender differences in response to periodontitis. Thus, we compared gender-specific differences in systemic cytokine concentrations in rats with and without ligature-induced periodontitis., Material and Methods: Experimental periodontal disease was initiated in Sprague-Dawley rats by placing a ligature around the crowns of the second right maxillary molar tooth. Sham-operated control groups were also created. Two weeks later, the right and left maxillary quadrants of teeth, liver and serum were collected from all the rats, and uterine horns were collected from the female rats. Liver and uterine samples were ground in phosphate-buffered saline (10 mg of tissue/mL of phosphate-buffered saline + protease inhibitor) containing a protease inhibitor, and cytokine concentrations were determined by enzyme-linked immunosorbent assay. Digital radiographs were made of maxillary quadrants, and the distance from cemento-enamel junction to alveolar crest was measured using image analysis software. Data were compared by factorial analysis of variance and a post-hoc Tukey test., Results: Female rats with ligatures had greater, but not significantly different, alveolar bone loss than males with ligatures. However, they had higher serum concentrations of interleukin-6, tumor necrosis factor-alpha and C-reactive protein, and liver C-reactive protein (p < 0.05). These females also had higher interleukin-6, tumor necrosis factor-alpha and vascular endothelial growth factor concentrations within the uterine horn, compared to female controls (p < 0.05). Male animals with ligatures had lower serum concentrations of C-reactive protein and higher interleukin-6 and tumor necrosis factor-alpha concentrations within serum, compared to male controls (p < 0.05)., Conclusion: Our study suggests that females with periodontal disease have a greater risk for inflammatory-based systemic diseases than males.