The role of apo B-100 as a transcription factor is indicated by the presence of regions in its primary structure that are similar to the DNA-binding domains of the transcription factors ISGF3, STATs, IRFs, and SREBPs as well as by the presence of 11 RNA-binding KH domains. The Apo B-100 sequence also contains numerous bipartite nuclear localization sequences (NLS). A modified gel shift assay was used to show binding of highly purified preparations of human LDLs to fragmented genomic DNA, plasmid DNA, synthetic oligonucleotides (ISRE, 5-GGGAAACCGAAACTG and E/C, E-box motif and CCAAT, adipocyte-specific genes promoter site), and total RNA from human liver. LDL was observed to bind preferentially to plasmid DNA containing the hCMV IE2 promoter region. In experiments using human liver total RNA, RNA for five different genes was recovered from LDL and VLDL bands. Gene transfection experiments using human skin fibroblast cells were used to study the gene transfer capacity of LDL. Cells transfected with a pEGFP-N1 plasmid DNA and LDL expressed functional GFP, as indicated by fluorescence, at approximately 3 hrs after transfection. Our results strongly support an alternative role for apo B-100, in toto or perhaps as functional fragments, in the control of gene expression and as gene transfer vector.