CCAAT/enhancer binding proteins (C/EBPs) are transcription factors that regulate a variety of cellular genes involved in broad range of physiological processes, including immune cell functions that involve cytokine expression and release as well as immune cell differentiation and inflammation. In addition, C/EBP factors regulate many viral promoters, including the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). The dependence of HIV-1 gene expression and replication on C/EBP factors in cells of myeloid origin positions these factors as important regulators of HIV-1 during the course of disease, because cells of monocyte/macrophage origin are critical components of viral pathogenesis in the peripheral blood and in other tissue compartments, including the central nervous system (CNS). Recent studies also indicate potentially important correlates between HIV-1 LTR C/EBP site sequence variation (which alters factor recruitment and activity), sequence compartmentalization, and the severity of HIV-1-induced immunologic dysfunction and neuropathogenesis. Cumulatively, studies of C/EBP factors and their roles in the regulation of host and viral gene expression indicate the importance of these factors in the progression of HIV-1-associated disease and, specifically, the genesis of CNS disease and HIV-1-associated dementia.