Background Salivary biomarkers of periodontitis were assessed longitudinally to determine response to therapy. Methods A 6-month case-controlled study of adults with chronic periodontitis was performed, with 33 participants receiving oral hygiene instructions (OHI) alone and 35 with scaling and root planing (SRP) combined with OHI. Saliva samples collected at week 0, 16 and 28 were analyzed for interleukin-1β (IL-1β), IL-8, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase-8 (MMP-8), osteoprotegerin (OPG) and tumor necrosis factor-α (TNF)-α. Clinical measures of periodontal disease were recorded at each visit. Results All parameters of periodontal health improved significantly in both groups by week 16 (p<0.0001) with the SRP group demonstrating greater benefit at week 16 and 28. Baseline OPG and TNF-α levels changed significantly at both follow-up visits (p<0.03), regardless of treatment group. IL-1β and MMP-8 levels decreased significantly from baseline (p≤0.04) in the SRP group only. OPG, MMP-8 and MIP-1α were significantly reduced in responders compared with non-responders (p=0.04, 0.01, 0.05 respectively). In receiver operating characteristic analyses, MMP-8 produced the highest area under the curve (≥ 0.7; p=0.01). Conclusion Salivary levels of IL-1β, MMP-8, OPG and MIP-1α reflected disease severity and response to therapy suggesting their potential utility for monitoring periodontal disease status.