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Background The effect of combined administration of multi-targeted receptor tyrosine kinase (RTK) inhibitor (sorafenib) and chemotherapy (pemetrexed) is still unknown.The cytotoxicity, the optimal combined modality and the mechanisms underlying the cytotoxic synergism between sorafenib and pemetrexed for EGFR TKI-resistant NSCLC cell lines were then investigated respectively.Methods A549 (EGFR wild-type and KRAS mutation), H1975 (EGFR mutation and KRAS wild-type) cell lines were treated with pemetrexed and/or sorafenib in vitro.IC50 values, CI (combination index), cell cycle distribution, phospho-p44/42MAPK were assessed respectively.Results The cytotoxic interactions between sorafenib and pemetrexed were dose dependent in EGFR TKI-resistant NSCLC cell lines.The administration of pemetrexed-sorafenib sequence had a synergistic effect and an advantage over sorafenib-pemetrexed sequence and concomitant administration in both cell lines.Cell cycle analysis showed that sorafenib arrested cells mainly in G 1 phase while pemetrexed arrested cell mainly in S phase.Exposure to sorafenib first induced G1 arrest and subsequently prevented the cytotoxicity of S phase specific drugs, pemetrexed.Exposure to pemetrexed resulted in an increased phospho-p44/42MAPK level which was inhibited by subsequent exposure to sorafenib.U0126, an inhibitor of the MAPK kinase also enhanced cytotoxicity of pemetrexed in a sequence dependent manner in TKI-resistant cell lines.Likewise,pemetrexed-activated MAPK signaling pathway was subsequently inhibited by U0126.Conclusions The sequence of pemetrexed followed by sorafenib had a synergistic effect and an advantage over other sequences in EGFR TKI-resistant NSCLC cell lines.The synergistic mechanism was due to sorafenib subsequently inhibiting the pemetrexed-activated, MAPK signaling pathway.The results may provide molecular evidence to support clinical treatment strategies for patients with EGFR TKI-resistant lung cancer.