We performed gene-expression profiling of PBMCs obtained from patients with familial hemophagocytic lymphohistiocytosis (FHL) to screen for biologic correlates with the genetic and/or clinical forms of this disease. Unsupervised hierarchical clustering of 167 differentially expressed probe sets, representing 143 genes, identified 3 groups of patients corresponding to the genetic forms and clinical presentations of the disease. Two clusters of up- and down-regulated genes separated patients with perforin-deficient FHL from those with unidentified genetic cause(s) of the disease. The clusterscomprised genes involved in defense/immune responses, apoptosis, zinc homeostasis, and systemic inflammation. Unsupervised hierarchical clustering partitioned patients with unknown genetic cause(s) of FHL into 2 well-distinguished subgroups. Patterns of up- and down-regulated genes separated patients with “late-onset” and “relapsing” forms of FHL from patients with an “early onset and rapidly evolving” form of the disease. A cluster was identified in patients with “late onset and relapsing” form of FHL related to B- and T-cell differentiation/survival, T-cell activation, and vesicular transport. The resulting data suggest that unique gene-expression signatures can distinguish between genetic and clinical subtypes of FHL. These differentially expressed genes may represent biomarkers that can be used as predictors of disease progression.