The predominant neuronal isoforms of the Oct-2 transcription factor, Oct 2.4 and Oct 2.5, repress the herpes simplex virus immediate-early promoter both in neuronal cells and in fibroblasts normally lacking Oct-2. In contrast, the predominant B lymphocyte form Oct 2.1, which is present at a lower level in neuronal cells, activates the immediate-early promoter in fibroblasts but represses it in neuronal cells. We show here that both Oct 2.4 and Oct 2.5 can functionally interact with Oct 2.1 and convert it from an activator into a repressor. Hence, the cell type-specific activity of Oct 2.1 results from the presence of Oct 2.4 and 2.5 in neuronal cells and their absence in other cell types. The significance of this effect is discussed in terms of the role of Oct-2 in the regulation of viral and cellular gene expression in neuronal cells.