Background: There is an ongoing controversy on the benefits of treatment protocols, including dental lasers and photodynamic 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 planing (SRP) in residual pockets.Methods: Thirty‐two individuals were included based on a history of previous treatment for periodontitis and the persistence of sites with probing depths >4 mm and bleeding on probing. Residual pockets were debrided with an ultrasonic device and then randomly 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: Compared with baseline, levels of interleukin‐17, basic fibroblast growth factor, granulocyte colony‐stimulating factor, granulocyte macrophage colony‐stimulating factor, and macrophage inflammatory protein 1‐α were lower 14 days and 2 months after treatment. Except for granulocyte colony‐stimulating factor, these differences remained significant throughout the observation period. The levels of five acute‐phase proteins (α‐2 macroglobulin, haptoglobin, serum amyloid P, procalcitonin, and tissue plasminogen 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 biochemical 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 mediators.