Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6gene fusions promoting constitutional upregulation of oncogenic EGR1-dependent gene expression. SFTs with the most common canonical NAB2exon 4 - STAT6exon 2 fusion variant (4-2) are more often located in the thorax (pleuro-pulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2exon 6 - STAT6exon 16/17 fusion variants (6-16/17) typically display a more cellular round to ovoid cell morphology and are more often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. In the current study, we employed next-generation sequencing based-gene expression profiling to identify significant differences in gene expression associated with anatomical localization and NAB2-STAT6gene fusion variants. SFTs with the 4-2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription and nuclear localization, whereas SFTs with the 6-16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating involvement of further co-transcription factors in the modification of chimeric NAB2-STAT6 dependent deregulation of EGR1-dependent gene expression. In summary, the current study establishes a potential molecular biologic basis for clinico-pathological differences in SFTs with distinct NAB2-STAT6gene fusion variants.