Dipeptidyl Peptidase IV (DPP IV) is an enzyme which splits N-terminal X-proline from peptides. The objective of this study was to present a reliable test to quantitatively estimate the serum Dipeptidyl Peptidase IV enzyme in oral cancer patients and to ascertain if Dipeptidyl Peptidase IV can be used as a tumor marker in the early diagnosis of cancer. The study was performed on 31 patients with different stages of oral squamous cell carcinoma as a study group and 10 control healthy group. The mean DPP IV activity in study group was significantly lower than control group. Among the study group, well differentiated squamous cell carcinoma had the highest mean serum DPP IV activity than moderately and poorly differentiated squamous cell carcinoma. We hence conclude that DPP IV activity in serum can be used as a biochemical marker in the diagnosis of oral squamous cell carcinoma.