Background: There is an ongoing controversy on the bene- fits of treatment protocols, including dental lasers and photo- dynamic therapy (PDT). The purpose of this study is to compare the local biologic effects of PDT, diode soft laser (DSL) therapy, and conventional deep scaling and root plan- ing (SRP) in residual pockets. Methods: Thirty-two individuals were included based on a his- tory of previous treatment for periodontitis and the persistence of sites with probing depths >4 mm and bleeding on probing. Resid- ual pockets were debrided with an ultrasonic device and then ran- domly assigned either to PDT, DSL, or SRP. Gingival crevicular fluid was collected before treatment, after 14 days, and at 2 and 6 months. Levels of 13 cytokines and nine acute-phase proteins were measured using a bead-based multiplexing analysis system. Results: Treatment with PDT, DSL, or SRP led to significant changes in several cytokines and acute-phase proteins: Com- pared with baseline, levels of interleukin-17, basic fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and macrophage inflam- matory protein 1-a were lower 14 days and 2 months after treat- ment. Except for granulocyte colony-stimulating factor, these differences remained significant throughout the observation pe- riod. The levels of five acute-phase proteins (a-2 macroglobulin, haptoglobin, serum amyloid P, procalcitonin, and tissue plas- minogen activator) were significantly higher at 6 months than at baseline. No significant differences were observed among the three treatment modalities at any time point for any bio- chemical parameter. Conclusions: Levels of several cytokines and acute-phase proteins significantly changed after treatment regardless of treatment modality. There was no evidence for a specific DSL- or PDT-enhanced expression of inflammatory media- tors. J Periodontol 2012;83:1018-1027.