The results showed that KRAS gene mutants were increased in 131I-resistant DTC patients; KRAS genemutation suppressed p21 protein expression and was associated with clinical stage and poor prognosis. In vivo and in vitro experiments proved that sub-lethal dose of 131I increased KRAS genemutation rate, suppressed p21 expression level, and caused 131I radiotherapy resistance. Reversely, over-expression of KRAS gene could significantly increase p21 expression, and inhibit tumor proliferation and metastasis.