Introduction: This study was designed to investigate overcoming gefitinib resistance in NSCLC with the T790M mutation of EGFR through a mechanism-based approach using simvastatin. Materials and Methods: We developed an in vitro model of acquired resistance to gefitinib by continuously treating HCC827 with escalating doses. The effects of simvastatin on apoptosis and AKT/Β-catenin signaling in gefitinib-resistant NSCLC cells were examined by annexin V binding assay and immunoblot analysis. We tested the effects of LY294002, siRNA and overexpression for AKT in simvastatin treated gefitinib-resistant NSCLC cells. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we knocked down the survivin level by introducing siRNA for survivin. Results: In H1975 and HCC827R, gefitinib-resistant NSCLC cells a significant increase in the expression of phosphorylated AKT and survivin compared to HCC827, EGFR-sensitive NSCLC cells was observed. We showed that simvastatin exerted a remarkable inhibitory effect on activation of AKT, leading to suppression of Β-catenin activity and expression of its targets, survivin and cyclin D1. Moreover, survivin down-regulation by RNA interference augmented apoptotic potential to simvastatin and gefitinib treated gefitinib-resistant NSCLC cells. Conclusions: Simvastatin could overcome gefitinib resistance in NSCLC with the T790M mutation of epidermal growth factor receptor via AKT/Β-catenin signaling dependent down-regulation of survivin.