BACKGROUND Glutathione S-transferase pi (GST-pi) is an enzyme that catalyzes the conjugation of electrophilic substrates and prevents oxidative damage. Although GST-pi expression has been analyzed in many cancers, the significance of GST-pi expression in nasopharyngeal cancer (NPC), a tumor with a high treatment failure rate, is still unclear. OBJECTIVE To elucidate the significance of GST-pi expression in NPC. METHODS Evaluation of GST-pi expression in NPC tissue specimens and determination of its relationship with tissue iron (a pro-oxidant) and clinicopathological factors in NPC. METHODS Immunohistochemical expression of GST-pi was carried out in 55 NPC and 4 normal nasopharyngeal tissue sections. Eleven nasopharyngeal biopsy specimens (4 normal and 7 NPC) were analyzed for tissue iron levels. The expression of GST-pi in NPC was correlated with corresponding tissue iron levels. The relationships between GST-pi expression with sex, race, tumor stage, cervical nodal status, and clinical staging were also analyzed. RESULTS Glutathione S-transferase pi immunoreactivity was observed in all NPC sections, with the percentage of immunopositive cells ranging from 1.0% to 72.0%. Tissue iron levels were significantly higher in the NPC tissues compared with normal tissues (P =.001). A direct correlation was observed between GST-pi expression and total and nuclear iron levels in NPC (P =.01 and P =.047, respectively). A significant association was also observed between GST-pi expression and cervical nodal disease (P =.007). CONCLUSIONS Nasopharyngeal tumor cells may respond to pro-oxidant conditions by modulating intracellular antioxidant defense. Glutathione S-transferase pi expression appears to be associated with lymphogenous metastasis in NPC.