Previously we have shown that (-)-epigallocatechin gallate (EGCG) can induce nonapoptotic cell death in human hepatoma HepG2 cells only under serum-free condition. However, the underlying mechanism for serum in determining the cell fate remains to be answered. The effects of fetal bovine serum (FBS) and its major component bovine serum albumin (BSA) on EGCG-induced cell death were investigated in this study. It was found that BSA, just like FBS, can protect cells from EGCG-induced cell death in a dose-dependent manner. Detailed analysis revealed that both FBS and BSA inhibited generation of ROS to protect against toxicity of EGCG. Furthermore, EGCG was shown to bind to certain cellular proteins including caspase-3, PARP, and α-tubulin, but not LC3 nor β-actin, which formed EGCG-protein complexes that were inseparable by SDS-gel. On the other hand, addition of FBS or BSA to culture medium can block the binding of EGCG to these proteins. In silico docking analysis results suggested that BSA had a stronger affinity to EGCG than the other proteins. Taken together, these data indicated that the protective effect of FBS and BSA against EGCG-induced cell death could be due to (1) the decreased generation of ROS and (2) the competitive binding of BSA to EGCG.