Background: This study aims to evaluate the effect of one‐stage full‐mouth ultrasonic debridement (OSFMUD) on clinical and immunoinflammatory parameters in smokers with generalized aggressive periodontitis (GAgP).Methods: Fourteen smoking and 14 non‐smoking patients with GAgP were selected. After initial supragingival therapy, patients were treated by OSFMUD. Full‐mouth parameters evaluated were: 1) plaque index (PI); 2) bleeding scores (BS); 3) probing depth (PD); and 4) clinical attachment level (CAL). Clinical evaluation was performed, and gingival crevicular fluid (GCF) was collected for selected sites (ss) at baseline and 1, 3, and 6 months. GCF was analyzed via enzyme‐linked immunosorbent assay for: 1) receptor activator of nuclear factor‐κ B ligand (RANKL); 2) osteoprotegerin (OPG); 3) interleukin (IL)‐6; and 4) tumor necrosis factor (TNF)‐α, whereas secreted osteoclastogenic factor of activated T‐cells (SOFAT) was evaluated by Western blotting.Results: Significant reduction (P <0.05) was observed between baseline and 6 months for: 1) PI; 2) BS; and 3) PD, with no difference between smoking and non‐smoking patients (P >0.05). Regarding CAL, only non‐smoking patients showed a significant decrease (P <0.05). Significant reduction (P <0.05) was observed in both groups for: 1) PIss; 2) PDss; 3) bleeding on probing; and 4) relative CAL. Smoking and non‐smoking patients presented significantly decreased levels of IL‐6 and TNF‐α over time (P <0.05); however, no difference was observed between groups (P >0.05). RANKL was significantly different (P <0.05) only for non‐smokers at 6 months, whereas OPG was not significant (P >0.05). SOFAT expression was significantly lower (P <0.05) after OSFMUD for non‐smokers only.Conclusion: Considering the clinical and immunoinflammatory parameters evaluated in this short‐term follow‐up study, it can be concluded that OSFMUD can be used as an alternative treatment for smokers with GAgP.