Background and Objectives: Behçet syndrome (BS) is a multisystemic inflammatory disorder of unknown etiology. Currently, BS is classified as a complex autoinflammatory disorder presenting with a variable vessel vasculitis. Inconsistent, sometimes contrasting immunological findings observed in BS studies and considerable geographic variation in BS’s disease expression are in need of explanation. Significant gene expression and molecular disease mechanisms differences were documented between BS clinical phenotypes. Such differences among patients of the same population brings to mind the case across different populations. This study aimed to compare gene expression profiles of Portuguese and Turkish BS patients. Materials and Methods: Publicly available (GEO repository) transcriptome datasets from Portuguese (GSE17114) and Turkish (GSE209567) BS cohorts were retrieved and analyzed. Differentially expressed genes (DEGs) were identified using p≤0.05 and fold-change (FC) thresholds of ≥1.5 and ≥2. BRB-ArrayTools for class comparisons, Venny 2.1.0 for Venn diagram analyses, Cluster 3.0 and Java Treeview for clustering analyses, and WebGestalt for functional enrichment analyses were used. Results: Substantial differences in DEG profiles were observed between Portuguese and Turkish BS patients. During the class comparison PBvs.TB (PB: Portuguese and TB: Turkish BS patients), 8024 DEGs were documented with an FC≥2. Venn diagram analysis showed no shared genes at the intersection PBvs.PC TBvs.TC (PC: Portuguese and TC: Turkish controls). Both populations demonstrated decreased anti-inflammatory gene expressions, albeit with distinct gene identities. A set of 20 genes including IFI27 successfully clustered PB&TB. No enriched gene ontology terms were shared during functional enrichment analyses. Conclusions: Significant molecular differences exist between Portuguese and Turkish BS patients. In addition to its complex genetic background, BS is a heterogeneous syndrome. Decreased expression of anti-inflammatory genes is common in BS. The identities of these genes are different across populations. Pro-inflammatory genes may further enhance disease severity in BS. A forthcoming era of personalized therapeutics based on molecular profiles may be approaching.