Background: Tumor necrosis factor-alpha (TNF-α), a ” major inflammatory cytokine,” not only plays an important role in periodontal destruction but also is extremely toxic to the host. Till date, there are not many studies comparing the levels of TNF-α in serum and its relationship to periodontal disease. Aim: Our study aimed to compare the serum TNF-α among the two study groups, namely, healthy controls and chronic periodontitis patients and establish a correlation between serum TNF-α and various clinical parameters. Hence, an attempt is made to estimate the level of TNF-α in serum, its relationship to periodontal disease and to explore the possibility of using the level of TNF-α in serum as a biochemical “ marker” of periodontal disease. Materials and Methods: Forty individuals participated in the study and were grouped into two subgroups. Group A – 20 systemically and periodontally healthy controls. Group B – twenty patients with generalized chronic periodontitis. The serum samples were assayed for TNF-α levels by enzyme-linked immunosorbent assay method. Results: The mean serum TNF-α cytokines for Group B Generalized chronic periodontitis (GCP) was 2.977 ± 1.011, and Group A (healthy) was 0.867 ± 0.865. The range of serum TNF-α was from (0.867 to 2.977). Serum TNF-α cytokines had highly significant correlation with all clinical parameters (plaque index, probing pocket depth, clinical attachment loss, and gingival index) among all study participants ( P = 0.001). Conclusion: These observations suggest a positive association between periodontal disease and increased levels of TNF-α in serum. It can be concluded that there is a prospect of using the estimation of TNF-α in serum as a “marker” of periodontal disease in future. However, it remains a possibility that the absence or low levels of TNF-α in serum might indicate a stable lesion and elevated levels might indicate an active site but only longitudinal studies taking into account, the disease “activity” and “inactivity” could suggest the possibility of using TNF-α in serum as an “Indicator” of periodontal disease.