Apoptotic resistance can either be desirable or undesirable, depending on the conditions. In cancer chemotherapy, it is critical that tumor cells are selectively and effectively killed while leaving normal cells undamaged. Since acquisition of apoptotic resistance appears to be a common occurrence during malignant transformation, elucidating the mechanisms underlying apoptotic resistance is an area of intense study. Previous studies have revealed that metallothionein (MT) can protect cells from apoptosis induced by oxidative stress and metals. In the present study, we tested the hypothesis that the presence of MT may somehow modulate apoptosis. Our results revealed a strong linear negative correlation between basal MT levels and etoposide-induced apoptosis in the human tumor cell lines PLC/PRF/5, H460, and HepG2 (r = −0.991). In HepG2 cells, 24 h pretreatment with cadmium resulted in concentration-dependent increases in MT levels and marked decreases in etoposide-induced apoptosis. Zinc pretreatment also resulted in increased MT synthesis and decreased etoposide-induced apoptosis. More importantly, induced MT levels were negatively correlated with sensitivity to etoposide-induced apoptosis (r = −0.965). These suggest that MT may play a role in regulating apoptosis and that modulating MT expression may provide a strategy for altering cellular resistance to chemotherapeutic compounds.