AimTo identify serum‐ and salivary‐derived inflammatory biomarkers of periodontitis progression and determine their response to non‐surgical treatment.Materials and MethodsPeriodontally healthy (H; n = 113) and periodontitis patients (P; n = 302) were monitored bi‐monthly for 1 year without therapy. Periodontitis patients were re‐examined 6 months after non‐surgical periodontal therapy (NSPT). Participants were classified according to disease progression: P0 (no sites progressed; P1: 1–2 sites progressed; P2: 3 or more sites progressed). Ten salivary and five serum biomarkers were measured using Luminex. Log‐transformed levels were compared over time according to baseline diagnosis, progression trajectory and after NSPT. Significant differences were sought using linear mixed models.ResultsP2 presented higher levels (p < .05) of salivary IFNγ, IL‐6, VEGF, IL‐1β, MMP‐8, IL‐10 and OPG over time. Serum analytes were not associated with progression. NSPT led to clinical improvement and significant reduction of IFNγ, IL‐6, IL‐8, IL‐1β, MMP‐8, IL‐10, OPG and MMP‐9 in saliva and of CRP, MMP‐8, MMP‐9 and MPO in serum.ConclusionsPeriodontitis progression results from a sustained pro‐inflammatory milieu that is reflected in salivary biomarkers, but less so in serum, likely because of the limited amount of progression per patient. NSPT can significantly decrease the levels of several salivary analytes.