Aim: The aim of this case–control study is to estimate the circulatory levels of tumor necrosis factor alpha (TNF-α) in saliva and serum of patients with chronic periodontitis and periodontally healthy subjects. Materials and methods: Forty-four patients were screened, and based on biofilm-gingival interface (BGI) index, they were grouped into group I healthy periodontium [BGI-H (20)] and group II periodontitis [BGI-P3 (24)]. Venous blood and salivary samples were collected and analyzed using solid-phase enzyme-linked immunosorbent assay. Independent sample t test was performed to determine the association. Results: Overall, there were differences in both the saliva and the serum TNF-α levels in healthy and periodontitis subjects. The average serum TNF-α concentration in group I healthy subjects was 23.12 pg/mL and in group II periodontitis was 24.06 pg/mL. In the saliva, the mean TNF-α level in group I healthy subjects was 45.69 pg/mL and in group II diseased subjects was 46.58 pg/mL. However, the values were not statistically significant (p > 0.05). Conclusion: Circulatory and salivary TNF-α levels were found in detectable quantities. They showed a marginal increase in chronic periodontitis patients when compared with normal healthy patients in the absence of systemic diseases. Further studies are required in a large scale and with different methodologies to substantiate the role of TNF-α in the progression of periodontal diseases. Clinical significance: Clinical significance of this study is to analyze the TNF-α levels in saliva and serum, which may be the aggravating factor in causing periodontal disease, thereby helping to treat periodontitis.