Smoking is one of the strongest predictors of attachment and bone loss. Smokers demonstrate reduced inflammatory clinical signs, which could be due to local vasoconstriction and increased gingival epithelial thickness. The byproducts originating from tobacco oxidation modify the clinical characteristics and progression of periodontal disease. The aim of this study was to investigate the relationship between the thickness of marginal gingival oral epithelium, sulcular bleeding, and vascular caliber and density of the microvessels in smokers and nonsmokers with and without periodontitis and to better understand the role of smoking in relation to periodontal disease. One hundred twenty individuals were enrolled in this study and divided into four groups comprising 30 participants each. The clinical measurements carried out included probing depth, clinical attachment loss, and bleeding index, along with gingival biopsy specimens, which were subjected to immunohistochemical and histomorphometric analysis. Correlation of the clinical and histologic features revealed that smokers presented with fewer inflammatory signs, had fewer vascular elements in the subepithelial connective tissue layer, and showed a resultant increase in epithelial thickness irrespective of the presence of periodontitis. There was a mean increase of epithelial thickness of 181.3 μm (suprapapillary epithelial thickness [SET]) to 380.2 μm (maximal epithelial thickness [MET]) in smokers with periodontitis as compared to 157.4 μm (SET) to 325.3 μm (MET) in nonsmokers with periodontitis. The mean microvascular density in smokers with periodontitis was 325.4 per mm2, which was found to be statistically significantly less than that of nonsmokers with periodontitis, who had a mean value of 412.13 per mm2. The vessel caliber also was reduced in smokers, with a mean value ranging from 4.7 to 6.1 μm compared with a mean of 6.2 to 9.2 μm in nonsmokers, irrespective of the presence of periodontitis. Statistically significant differences were found in vascular density and thickness of gingival epithelium between smokers and nonsmokers with and without periodontitis. These differences may impact the progression of periodontal disease.