Objective. Granulomatosis with polyangiitis (GPA), formally known as Wegener's granulomatosis, is a systemic vasculitis with necrotizing granulomatous inflammation. As treatment directed against tumor necrosis factor (TNF)-α failed in GPA, we investigated whether "TNF-α signature" (i.e. gene expression profile of TNF-α activation) was present in peripheral blood mononuclear cells (PBMCs) of patients with GPA. Methods. Gene expression profiling was performed using total RNA from PBMCs of 41 patients with GPA and 23 healthy control subjects using the Illumina microarray technique. Gene set enrichment analysis (GSEA) was performed to detect the presence of TNF-α signature using the curated list C2-V3.0 by the Broad Institute. False discovery rate＜0.05 was considered statistically significant. Results. GSEA did not show significant enrichment of any TNF-α associated gene sets in GPA. Expression levels of genes up-regulated by TNF-α did not differ between healthy control subjects, patients in remission (Birmingham Vasculitis Activity Score [BVAS]=0), and those with active disease (BVAS≥1). In addition, an unsupervised hierarchical clustering of those genes failed to cluster the samples into healthy control subjects and GPA in remission or with active disease. B cell activation signature was enriched in GPA patients. Conclusion. Absence of a TNF-α signature in PBMCs may suggest that TNF-α plays a less important role in the pathogenesis of GPA than previously accepted. (J Rheum Dis 2015;22:293-297)