Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. In order to advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells (PBMCs) from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with 2.5-fold difference in expression (P = 0.05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, pro-apoptotic proteins, and B- and T-cell differentiation were down-regulated in patients with FHL. Genes associated with the canonical pathways of IL-6, IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of anti-apoptotic proteins were overexpressed in patients with FHL. This, first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underly the immunobiology of FHL.