CCAAT/Enhancer Binding Protein d (C/EBPd) plays a key role in mammary epithelial cell G0 growth arrest and “loss of function” alterations in C/EBPd have been reported in breast cancer and acute myeloid leukemia (AML). C/EBPd is regulated at the transcriptional, post-transcriptional and post-translational levels, suggesting tight control of C/EBPd content and function. Protein inhibitors of activated STATs (PIASs) regulate a growing number of transcription factors, including C/EBPs. HC11 nontransformed mammary epithelial cells express PIAS3, PIASxß and PIASy and all three PIAS family members repress C/EBPd transcriptional activity. PIASy is the most potent however, repressing C/EBPd transcriptional activity by >80%. PIASy repression of C/EBPd transcriptional activity is dependent upon interaction between the highly conserved PIASy N-terminal nuclear matrix binding domain (SAPD) and the C/EBPd transactivation domain (TAD). PIASy repression of C/EBPd transcriptional activity is independent of histone deacetylase activity, PIASy E3 SUMO ligase activity and C/EBPd sumoylation status. PIASy expression is associated with C/EBPd translocation from nuclear foci, where C/EBPd co-localizes with p300, to the nuclear periphery. PIASy-mediated translocation of C/EBPd is dependent upon the PIASy SAPD and C/EBPd TAD. PIASy reduces the expression of C/EBPd adhesion-related target genes and enhances repopulation of open areas within a cell monolayer in the in vitro “scratch” assay. These results demonstrate that PIASy represses C/EBPd by a mechanism that requires interaction between the PIASy SAPD and C/EBPd TAD and does not require PIASy SUMO ligase activity or C/EBPd sumoylation. PIASy alters C/EBPd nuclear localization, reduces C/EBPd transcriptional activity and enhances cell proliferation/migration.