Background: Periodontitis is initiated by the presence of bacterial biofilm, which triggers host inflammatory response. Syndecans (Sdcs) belong to a family of cell surface heparan sulphate proteoglycans (HSPGs), which are known to have versatile roles in regulation of the inflammatory response. Materials and methods: 40 samples of human gingiva were obtained for this study: 20 samples from subjects with untreated generalized periodontitis and 20 samples from healthy controls. Samples were stained for immunofluorescence (IF) to Sdcs (Sdc1, Sdc2, Sdc4), HS enzymes (EXT1, EXT2, NDST1, NDST2, HPSE1) and general inflammatory cell marker CD45. High-resolution panoramic (IF) images of gingiva samples were analyzed by IF signal quantification methods. Histograms for acquired images were exported as tables, which were then used to calculate the size of expression domains. Single factor ANOVA was used for comparison of expression domains between the groups. Correlation of expression domains was done by multiple linear regression. Results: The initial comparison of group means for total expression domain of all investigated factors revealed that only EXT1 is differentially regulated in periodontitis (p=4, 5519×10-6). Comparison of group means of expression domains in epithelial and stromal compartments revealed differences: stromal expression domains of Sdc1 (p=1, 1033×10-6), HPSE1 (p=0, 0023), EXT1 (p=1, 2849×10-7), NDST1 (p=0, 000105), and CD45 (p=0, 003747) showed significant difference between controls and periodontitis group. Conclusions: The expression profiles of Sdcs and HS enzymes differentially correlate with the presence of inflammatory infiltrate in healthy and diseased periodontal tissue, which might imply that the investigated factors could be involved in modulation of inflammatory response in periodontitis.