Oral cancer is popular in India, Taiwan and many other countries. However the immunopathogenesis of oral cancer is not fully clarified. Objectives: To investigate alteration of lymphocyte populations in oral cancer and precancer Taiwaness patients. Methods: We analyzed the lymphocyte populations (CD3+/CD4+ T cells, CD3+/CD8+ T cells, CD19+ B cells and CD56+ NK cells and their activation marker CD69) in healthy Taiwanese (male: 80, female: 50), and patients with oral cancer (male: 87, female: 10) and precancerous lesions (28 patients) using flow cytometry. Results: A marked increase in NK cell (CD56+), CD4+/CD69+ T cell, CD19+/CD69+ B cell and CD56+/CD69+ NK cell populations in oral cancer patients were found when compared with healthy persons. On the contrary, the lymphocyte populations expressing CD19+ and CD19+/CD25+ markers were decreased in oral cancer patients relative to that of healthy persons. Evident increase in NK cells (CD56+) and B cells (CD19+) was also noted in lymphocytes isolated from patients with oral precancerous lesions. In addition, an increase in CD56+/CD69+ NK cells was noted in recurrent oral cancer when compared with fresh oral cancer cases. However, oral habits (betel quid chewing, alcohol and smoking), tumor location, tumor size and differentiation status of tumor cells alone showed little effect on lymphocyte populations. Conclusion: These results suggest that alterations in T cell, B cell and NK cell populations are crucial in the pathogenesis of oral cancer. Analysis of lymphocyte populations is a useful biomarker predicting different stages of oral carcinogenesis.