TSG101 protein is one of the key factors in Endosomal sorting pathway. The abnormality of this pathway could decrease degradation of Notch receptor which leads to disorder of cell differentiation and development in drosophila. In mammal, the Notch3 receptors correlate with lung tissue development and lung carcinogenesis. The purpose of this study is to explore the relationship between TSG101 protein and Notch3 receptor in human lung cancer.Immunohistochemical method (S-P method) and Western blot were applied to detect the expressions of TSG101 protein and Notch3 receptor in lung cancer tissues and cell lines, in comparison with the corresponding normal tissues and cell lines. Besides, the expression of Notch3 receptor was observed when TSG101 protein was blocked by its specific antibody.The TSG101 protein expressions in tumor tissues were significantly lower than those in the neighboring noncancerous tissue, with higher expressions of Notch3 receptor in tumor tissues, which were correlated with the cellular differentiation and lymph node metastases. The expression of Notch3 receptor increased after blockage of TSG101 protein by its specific antibody.Down-regulation of TSG101 protein was correlated with the up- regulation of Notch 3 receptor in lung cancer.