To determine whether the human (h) NQO1 (NAD(P)H: quinone oxidoreductase 1) gene contains DNA sequences that directly mediate its high and low expression in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), respectively, a series of deletion constructs spanning up to -4kb of the 5(') flanking region of hNQO1 was used in transient transfection assays. The antioxidant response element (ARE) was found to be critical to the elevated expression of NQO1 in NSCLC. However, the ability of both heterologous and deletion promoter constructs to confer ARE responsiveness demonstrated that SCLC contains the necessary program/menu of transcription factors responsible to drive hNQO1 expression via the ARE. By examining the regulatory region of the hNQO1 gene, we identified a proximal repressor region between -259 and -131. These results provide the first evidence of a proximal repressor region exerting a negative role on the regulation of the hNQO1 promoter in SCLC.