Long noncoding RNAs (lncRNAs) are emerging as major regulators of a variety of cell signaling processes. Many lncRNAs are expressed in immune cells and appear to play critical roles in the regulation of immune response. Here， we have investigated the potential role of a well-known lncRNA， HOTAIR， in inflammatory and immune response. Our studies demonstrate that HOTAIR expression is induced in immune cells (macrophages) upon treatment with lipopolysaccharide (LPS). Knockdown of HOTAIR reduces NF-κB-mediated inflammatory gene and cytokine expression in macrophages. Inhibition of NF-κB resulted in down-regulation of LPS-induced expression of HOTAIR as well as IL-6 and iNOS expression. We further demonstrated that HOTAIR regulates activation of NF-κB and its target genes (IL-6 and iNOS) expression via facilitating the degradation of IκBα. HOTAIR knockdown reduces the expression of NF-κB target gene expression via inhibiting the recruitment of NF-κB and associated cofactors at the target gene promoters. Taken together， our findings suggest that HOTAIR is a critical player in NF-κB activation in macrophages suggesting its potential functions in inflammatory and immune response.