The anti-cancer properties of the green tea-derived mixture Polyphenon E (Poly E) have been demonstrated in a variety of cell culture and animal models. We recently discovered that the H460 lung cancer cell line is markedly resistant to the growth inhibitory effects of Poly E compared with SW480 colon and Flo-1 esophageal cancer cells. We investigated the mechanism of H460 resistance by comparing gene expression profiles of Poly E-sensitive and -resistant cells. Unsupervised hierarchical clustering revealed that Poly E-sensitive cells clustered separately from Poly E-resistant cells, and 6,242 genes were differentially expressed between the two groups at the 0.01 level of significance. We discovered that BCL2 gene and protein expression were significantly higher in H460 cells compared with SW480 and Flo-1 cells (10.60-fold higher gene expression; P < 0.0001). Inhibition of BCL2 expression and activity, using siRNA and the small molecule inhibitor HA14-1 respectively, restored sensitivity to Poly E and induced BCL2-related apoptosis by decreasing mitochondrial membrane potential and inducing PARP cleavage. Our results suggest that increased BCL2 expression may contribute to H460 resistance to the growth inhibitory effects of Poly E. If validated in additional laboratory and clinical models, BCL2 could ultimately be used as a marker of Poly E resistance.