In addition to their conventional G-C/T target sequences, Sp1 family transcription factors (Sp-factors) can interact with a subset of the target sequences for NFκB. Due to the low level of bona fide NFκB activity in most resting cells, this interaction between Sp-factors and κB-sites could play important roles in cell function. Here we used mutagenesis of a canonical κB element from the immunoglobulin and HIV promoters to identify the GC-rich sequences at each end required for Sp-factor targeting. Through screening of multiple κB elements, a sequence element located in the second intron of superoxide dismutase-2 (SOD2) was identified as a good candidate for both NFκB and Sp-factor binding. In neurons, the prominent proteins interacting with this site were Sp3 and Sp4, whereas Sp1, Sp3, and NFκB were associated with this site in astroglia. The neuronal Sp-factors repressed transcriptional activity through this κB-site. In contrast, astroglial Sp-factors activated promoter activity through the same element. NFκB contributed to control of the SOD2 κB element only in astrocytes. These findings imply that cell-type specificity of transcription in the central nervous system, particularly with regard to κB elements, may include two unique aspects of neurons: 1) a recalcitrant NFκB and 2) the substitution of Sp4 for Sp1.