Background: Osteopontin (OPN) is a bone matrix derivative, whose levels reflect active lesions of aggravated periodontal disease accompanied by alveolar bone resorption. OPN is also a component of human atherosclerotic plaque, suggesting a role of OPN in cardiovascular diseases. The present study was conducted to assess and compare plasma OPN levels in subjects with healthy periodontium and generalized chronic periodontitis and to evaluate the effect of scaling and root planing on Plasma OPN levels of generalized chronic periodontitis subjects. Materials and Methods: 40 gender matched subjects were divided into two equal groups, Group I‑ Healthy and Group II‑ Generalized chronic periodontitis, based on the Periodontal Disease Index. Blood samples were collected from the subjects at the time of clinical examination (Group I, II) and two months after Scaling and Root planning of Group II. Plasma OPN level was determined using a OPN Enzyme Immunometric Assay Kit (Quantikine). Results: The mean value of plasma OPN levels in subjects with generalized chronic periodontitis was higher (153.08 ng/ml) as compared to the subjects with Healthy periodontium (55.09 ng/ml). After treatment of generalized chronic periodontitis group, the level of plasma OPN decreased to 91.53 ng/ml. Conclusion: The findings from the study suggest that Plasma OPN levels were highest in plasma from sites with periodontal destruction; however, scaling and root planing resulted in the reduction of OPN levels.