Drug resistance is one of the major causes in treatment failure of non-small cell lung cancer. Interactions between tumor cells and extracellular matrix have been shown to be one of the mechanisms. We investigated the expression of extracellular matrix proteins and the effects of collagen IV on cisplatin-induced apoptosis in cisplatin-sensitive and -resistance lung cancer cells. Extracellular matrix may provide protection against cisplatin-induced apoptosis of lung cancer cells. Integrin β(1) signaling and PI3-Kinase pathway may be important survival pathways of drug-induced apoptosis in lung cancer cells, and activation of this pathway may contribute to the generation of drug resistance.