Background and Objectives: The aim of this study was to evaluate and compare the effects of two different anti-inflammatory drugs (ketoprofen and prednisone) combined with an antibiotic (amoxicillin + clavulanic acid) and periodontal surgery on dental and periodontal parameters in patients with severe chronic periodontitis. In addition, salivary stress expressed by cortisol levels was assessed. Materials and Methods: An interventional study was performed on 22 periodontal subjects and 19 clinical healthy controls. The patients were divided in four groups, depending on treatment planning, as follows: eight patients received prednisone and antibiotherapy, associated with surgical periodontal therapy; seven patients received ketoprofen and antibiotherapy, associated with surgical periodontal therapy (group II); seven patients received only prednisone. Periodontal healthy patients underwent routine scaling and polishing. Bleeding on probing (BOP), dental mobility and salivary cortisol (ng/mL) were assessed before and after treatment. The means and standard deviations for the salivary cortisol levels (SCLs), dental and periodontal parameters were calculated for all groups using each patient as a unit of analysis. Results: Data analyses showed that the two different anti-inflammatory drugs associated with or without surgical therapy were efficient on inflammation periodontal parameters (BOP, dental mobility). Prednisone treatment alone was associated with a significant decrease of SCLs between pretreatment and post-treatment. Conclusions: In the present study, the effects of either of the anti-inflammatory drugs on inflammation evolution and salivary stress were comparable in patients undergoing antibiotherapy and surgical periodontal therapy.