The LDL receptor, which mediates the cellular uptake of cholesterol, is subject to classic end-product repression when cholesterol accumulates in the cell. We here show that the sensitivity to end-product repression depends upon a 42 bp element in the 5'-flanking region of the human LDL receptor gene. This sequence, designated sterol regulatory element 42 (SRE 42), contains two 16 bp direct repeats that exhibit positive and negative transcriptional activities. Cells transfected with a fusion gene containing SRE 42 inserted into the promoter of the herpes simplex viral TK gene produced abundant mRNA when grown without sterols. When sterols were present, the mRNA was reduced by 57%-95%, depending on the number of copies of SRE in the fusion gene. These transfection data plus DNAase I footprinting experiments suggest a model of end-product repression in which the end product (sterols) opposes the action of a positive transcription factor that binds to a discrete promoter element.