Background and purpose: In the context of EGFR-targeting strategies we investigated autocrine/paracrine factors leading to in vitro radioresistance of K-Ras mutated tumor cells through activation of EGFR mediated signal transduction. Patients and methods: Ras mutated (Ras_mt) and normal Ras (Ras_wt) presenting human tumor cell lines were used to analyze the potential of conditioned media (CM) of both cell types to mediate radioresistance and to activate EGFR-signaling cascades. Therefore, clonogenic assays as well as SDS-PAGE combined with immunoblotting was performed. Additionally, Ras-mutated cells were transfected with K-Ras-siRNA to investigate, how downregulation of mutated K-Ras affects secretion of EGFR-ligands, stimulation of EGFR-signaling and modulation of radiation response. Results: TGFα, Amphiregulin (ARG) and CM from Ras_mt cells (Ras_mt-CM) resulted in an increased clonogenic survival of irradiated Ras_wt cells. Both, EGFR ligands as well as Ras _mt-CM led to a strong phosphorylation of EGFR and activation of downstream pathways, i.e. PI3K-AKT. However, neutralization of TGFα or ARG in Ras_mt-CM led to a marked reduction of P-AKT. Furthermore, Ras_mt-CM from K-Ras-siRNA transfected Ras_mt-cells markedly inhibited phosphorylation of AKT in Ras_wt cells and enhanced radiation sensitivity of A549 cells transfected with the siRNA. Conclusion: The data suggest that constitutively upregulated autocrine/paracrine secretion of EGF receptor ligands, especially ARG from K-Ras mutated cells, mediates radioresistance in Ras_mt-cells through stimulation of EGFR-PI3K-AKT pathway.