Distinction of high-grade esthesioneuroblastomas from other poorly differentiated tumors arising in the nasal cavity is an important diagnostic challenge because it determines patient management and prognosis. The human achaete-scute homologue (hASH1) gene is critical in olfactory neuronal differentiation and is expressed in immature olfactory cells; therefore, it could have potential use as a diagnostic marker. The aim of the present study was to determine the value of hASH1 messenger RNA (mRNA) levels in differentiating esthesioneuroblastoma from other poorly differentiated tumors. A real-time polymerase chain reaction assay was developed, permitting the comparative determination of hASH1 mRNA levels in triplicate in a double-blind pilot study including 24 frozen cases of esthesioneuroblastoma and poorly differentiated tumors. All 4 positive cases were esthesioneuroblastomas, and all 19 poorly differentiated tumors were negative. In addition, there was an inverse association between the grade of esthesioneuroblastomas and hASH1 mRNA levels. The hASH1 mRNA level might represent a useful tool for distinguishing esthesioneuroblastoma from poorly differentiated tumors of the sinonasal region.