Updated project metadata. This prospective study aimed to investigate salivary proteome changes in periodontitis patients in response to treatment. Ten systemically healthy, non-smokers with stage III, grade C periodontitis (32-43yrs, F:M:5:5) underwent non-surgical periodontal treatment. Saliva (n=30) was collected pre- (T0), and one (T1) and six (T6) month post-treatment. Whole-mouth plaque (PI) and gingival index (GI), probing depth (PD), bleeding on probing (BOP) and clinical attachment loss (CAL) were measured. The saliva proteome was investigated by label-free quantitative proteomics. Normalized protein intensities were measured and protein changes modeled over time (linear model) with significant protein regulation considered at false discovery rate (FDR)<0.05. Treatment significantly reduced PI, GI, BOP, percentages of sites with PD≥5mm and PD≥5mm+BOP (T1vsT0 and T6vsT0), PD and CAL (T6vsT0). Overall, 1713 proteins (5927 peptides) were identified. Following analysis, considering proteins quantified by ≥2 peptides, resulted in 878 distinct proteins. At T1, 80 (T1vsT0:60↑:20↓), and at T6, 118 human proteins (T6vsT0:67↑:51↓) were regulated. Top-regulated disease categories were shared between T1vsT0 and T6vsT0, with highest activity patterns for ‘cellular movement’. The post-treatment proteome (T6vsT1) remained stable. Periodontal treatment reduced clinical disease parameters and these changes were reflected in the salivary proteome.