Objectives: Recent literature has demonstrated that local proteolytic enzymes participate in periodontitis and peri-implantitis. The aim of the present study was to evaluate whether the serine proteases urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor type 1 (PAI-1) show elevated amounts in inflamed periodontal tissues as compared to healthy oral mucosa to determine if these proteins are involved in the process of peri-odontal breakdown. Method and Materials: Fifty-eight patients with severe periodontitis were included in this study. Periodontal therapy was performed by means of modified Widman flaps. During surgery, samples of healthy oral mucosa and inflamed tissues were taken. Highly sensitive ELISAs allowed for determination of uPA and PAI-1 content in inflamed periodontal tissues and healthy oral mucosa. Results: The amount of uPA and PAI-1 in diseased periodontal tissue was significantly higher than in the clinically healthy oral mucosa (P<= .002). However, no statistically significant correlation with the sex or age of the patients or attachment loss of the teeth was seen. Conclusion: Serine proteases uPA and its inhibitor PAI-1 participate in periodontitis. (Quintessence Int 2010; 41:165-171)