Background. Oral health is a substantial subject in human health which poor hygiene can cause a disturbance in the body. Periodontitis is an inflammatory oral DISEASE that etiology factors have a critical role in it; like microorganisms and host immune response. Fluctuation expression of Immune BIOMARKERS in developmental of this DISEASE is beneficial in periodontitis diagnostic. Methods. Published articles were accomplished from PubMed, Google Scholar, Wiley, Springer, Science Direct and Elsevier from 2012 to June 2019. Entirely, 45 articles were found and related ones reviewed. Results. Not only microorganisms have a key role in the initiation of this DISEASE but also immune response affects like double edge knife in progression and recurrence. BIOMARKERS are an imperative mediator in the immune system that accomplishes many functions in the body can initiate or promote periodontitis DISEASE. Varied Cytokines such as IL-1β , IL-6, IL-17, IL-18, IL-21, and TNF-β are a critical diagnostic marker in diagnostic of PERIODONTAL DISEASE. It is proved that with the severity of periodontitis the IL-1β and IL-6 levels increased, whereas the TNF-β levels decreased. Also, post stimulation IL-1 β and IL-6 levels were higher in patients with improved treatment outcome. Conclusions. Periodontitis is a convoluted inflammatory DISEASE that affects the quality of life which immune BIOMARKERS have a critical role in the procedure and stage of this DISEASE. Study and assessment of these immunomodulators in laboratory can help to rapid diagnosis and specificity treatment of periodontitis in clinic.