The tyrosine hydroxylase (TH) gene promoter contains adjacent octamer and heptamer motifs which act as target sites for octamer binding transcription factors. Mutation of the heptamer motif but not the octamer motif enhances TH promoter activity in neuronal cells expressing Oct-2 but not in non-expressing fibroblasts. Similarly addition of the heptamer motif to a minimal TH promoter represses gene expression in neuronal cells but not in fibroblasts. These effects can be reproduced by the artificial expression of neuronal isoforms of Oct-2 in fibroblasts which results in the repression of transfected TH promoters containing an intact heptamer motif but not those in which this motif has been mutated or deleted. The TH promoter thus represents the first example of a cellular promoter which is repressed by Oct-2. The significance of this effect is discussed in terms of the cell type specificity of the TH promoter and its induction by different physiological stimuli.