OBJECTIVE: Because of their rarity, it is not known whether isocitrate dehydrogenase 2 (IDH2) mutations are related to the occurrence of olfactory neuroblastoma (ONB). We investigated the relationships between IDH2 mutations, clinicopathological parameters, and the prognosis for ONB to establish a molecular classification using IDH2 mutations. METHODS: An 82-patient cohort was retrospectively screened using immunohistochemistry with a mutation-specific IDH2 antibody and real-time polymerase chain reactions for IDH2 mutations. We also immunohistochemically determined the expression of chromogranin A, synaptophysin, neuron-specific enolase, CD56, S100, and Ki-67. RESULTS: The 2 methods used for the detection of IDH2 mutations had high consistency. Mutation of IDH2 detected by real-time polymerase chain reaction correlated with higher Kadish stage, Hyams grade, and Ki-67 proliferation index. Mutation of IDH2 correlated negatively with the expression of chromogranin A, synaptophysin, CD56, and S100. Kaplan-Meier analysis showed that an IDH2 mutation, a high Hyams grade, and high Ki-67 proliferation index were associated with poor overall survival. The Hyams grade and IDH2 mutation were independent prognostic factors on multivariable analysis. CONCLUSIONS: Immunohistochemistry was a reliable method to assess the mutation status of IDH2. Tumors with IDH2 mutations represented a distinct subset with aggressive behavior and conferred a poor prognosis. The gene status of IDH2 could be a major molecular classification criterion in ONB.