Background The aim of the study was to evaluate Semaphorin-4D (SEMA-4D), Peptidylarginine deiminase-2 (PAD-2) and Matrix metalloproteinase-8 (MMP-8) levels of Gingival crevicular fluid (GCF) in periodontally healthy, stage III periodontitis smoker and non-smoker patients before and after Non-surgical periodontal therapy (NSPT). Methods 60 patients, with an equal allotment ratio for 3 groups of periodontally healthy (Group I), Non-smokers and smokers with stage III periodontitis (Group II and

more »

... up III) were evaluated for clinical and biochemical parameters in GCF for levels of SEMA-4D, PAD-2 and MMP-8 through enzyme linked immunosorbent assay (ELISA). Patients were subjected to NSPT and the 3 months post therapy levels were examined. Results Group III exhibited higher values of PPD (8.06 ± 0.19 mm), CAL (8.94 ± 0.19 mm), PI (2.58 ± 0.19) while lower PBI (1.39 ± 0.19%) and GI (1.72 ± 0.19) scores as compared to Group II, which reduced significantly from baseline to 3 months in both the groups after NSPT. For SEMA-4D, PAD-2 and MMP-8 levels in GCF, minimum values were seen for Group I which increased incrementally to Group II and III. Also, the SEMA-4D, PAD-2 and MMP-8 levels in GCF significantly reduced from baseline to 3 months amongst Group II and III. Conclusion The results indicate increased GCF levels of SEMA-4D, PAD-2 and MMP-8 in Group II and III, thereby implying that these molecules play a crucial role in the pathogenesis of periodontal diseases. Clinical Relevance: SEMA-4D, PAD-2 and MMP-8 may be suitable biomarkers of the periodontal status in future.