Background: Mast cells are the major effector cells that mediate IgE-dependent allergic reactions via high-affinity IgE receptors. We sought to use integrated network analysis to identify genomic biomarkers associated with high response in IgE-mediated activation of primary human mast cells. Methods: Primary human mast cell cultures derived from a cohort of 262 normal donors were categorized into High, Average and Low responder groups according to their activation response profiles. Microarray analysis followed by qPCR was used to identify genes that were differentially expressed in different responder cultures in their baseline conditions. The data were analyzed by constructing personalized perturbed profile (PEEP). Results: Data derived from qPCR validation of 8 selected genes that exhibited differential expression in the High responder group showed extensive heterogeneity. For upregulated genes, construction of PEEP for each individual sample of all 3 responder groups revealed that High responders exhibited higher percentage of “perturbed” samples whose PEEP values lied outside the normal range of expression. Moreover, the integration of PEEP of 4 selected upregulated genes into distinct sets of combinatorial profiles demonstrated that the specific pattern of upregulated expression of these 4 genes, in a tandem combination, was observed exclusively among the High responders. Conclusion: PEEP analysis was used to integrate the PEEP of a set of signature genes to construct a distinct combinatorial gene expression pattern for each individual sample. Such combinatorial approach was useful in identifying a set of genomic biomarkers that are associated with high degranulation response in human mast cell cultures derived from the blood of a cohort of normal donors.