The optimal administration time when tyrosine kinase inhibitor (TKI) combined with radiotherapy is unclear until today.To investigate the efficacy of combining erlotinib with radiation in different treatment schedules.We demonstrated that erotinib was administered to A973 lung cancer cells in three different ways (method Ⅰ: irradiation before administration, method Ⅱ: administration upon irradiation, method Ⅲ: irradiation after administration) to establish the radiosensitizing effect.The cell-survival rates were evaluated by colony-forming assays.The cell apoptosis was investigated using FCM, meanwhile, the expression of C-MET, p-C-MET and p-AKT expression after 6Gy irradiation and/or erlotinib were determined by Western blot analysis.The SER of the erlotinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.21, 1.52, and 1.31 respectively.A higher apoptosis rate was observed in cells at the 48h after exposure to 6 Gy irradiation dose when irradiation was delivered after erlotinib group.Increased cell apoptosis were further supported by the expression changes of C-MET,p-C-MET and p-AKT expression at the same time.The proteins expression was increased in the combination groups and change trends were negative to the cell apoptosis.To conclude, the radiosensitive effect of erlotinib was different following different schedule and it was related to PI3K signal transduction, further, the PI3K signal transduction maybe has regulation effect on it.