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Background: Expression of major histocompatibility complex class I-related chain A/B (MICA/B) has been intended to play a significant role in tumor immunosurveillance. Downregulation of MICA/B expression in tissues and augmented sera levels are assumed to impair the antitumor immune response. Method and results:In this study, the potential of sMICA as a marker for oral cancer (OC) was investigated. The sMICA levels in sera, saliva, and urine of OC patients were significantly different from those of the control group. The sMICA was correlated with tumor stage to evaluate the diagnostic power of MICA as a marker. However, the findings indicate that the expression of MICA/B in positive control and Stage I and IV showed significant difference as per one-way analysis of variance (P value <0.0001). Serum levels of sMICA showed a significant difference in the positive control and stages I and IV (P value <0.0001). MICA/B expression in patients with Stages II and III also showed a significant difference compared to positive control (P value of 0.0028 and 0.0003). Analysis of sMICA in serum, saliva and urine from OC patients showed significantly (P value <0.0001) higher levels (median 34.25 ± 3.57 pg/ml in pre-treatment sera, 193.93 ± 1.95 pg/ml in saliva and 109.89 ± 1.59 pg/ml in urine) than in control (median <1.2 pg/ml). Patients with poorly differentiated tumors exhibited a smaller amount of sMICA levels and well-differentiated tumors revealed higher levels of sMICA in biofluids. Conclusion:The release of sMICA and its expressions in biofluids reflect an impairment of tumor immunity. The sMICA levels may provide useful additional information for the diagnosis, staging and prognosis of cancer.