The phosphorylation of EGFR^Thr654 is required for nuclear EGFR importing, and our previous study has shown that pEGFR^Thr654 is an independent prognostic factor for the low survival rate of patients with cervical squamous carcinoma. Now, we aim to examine the role of pEGFR^Thr654 in the activation of DNA-PK and radio resistance. Either CaSki or HeLa cells were exposed to a dose of 4 Gy with a 6 MV X-ray in the presence or absence of Cetuximab or Gefitinib, then EGFR, pEGFR^Thr654, DNA-PKcs and pDNA-PK^Thr2609 levels were determined using a western blot. DNA damage was quantified with γH2AX foci analysis and the response of CaSki and HeLa cells to irradiation was determined using a colony formation assay. In CaSki and HeLa cells, irradiation induced nuclear EGFR accumulation, and pEGFR^Thr654 and pDNA-PK^Thr2609 levels were both significantly increased. Cetuximab pre-treatment significantly reduced the expression of pEGFR^Thr654 and pDNA-PK^Thr2609 and enhanced the γH2AX foci per cell and sensitivity enhancement ratio in CaSki cells. Gefitinib pre-treatment had a similar but weaker effect. In HeLa cells, similar effects of Cetuximab and Gefitinib on pEGFR^Thr654 and pDNA-PK^Thr2609 were observed, and no significant difference was found. We found that Cetuximab had a better effect than Gefitinib on attenuating the radio resistance in cervical squamous carcinoma cells via inhibiting pEGFR^Thr654-mediated nuclear EGFR transport and related DNA-PK^T2609-mediated DNA repair. However, in adenocarcinoma cells, both EGFR-targeted drugs had no remarkable effects on the radio sensitivity. Taken together, radiotherapy combined with Cetuximab may be a promising strategy to improve the therapeutic gain for cervical squamous carcinoma patients.