OBJECTIVES: Post-viral olfactory dysfunction (PVOD) is a neurogenic disorder caused by a common cold virus. Based on the homology of deduced amino acid sequences, olfactory sensory neurons (OSNs) in both mice and humans express either class I or class II odorant receptor genes encoding class I and class II OSNs. The purpose of this study was to determine whether OSN damage in PVOD occurs uniformly in both neuron types. MATERIALS AND METHODS: The characteristics of PVOD patients were compared with those of patients with chronic rhinosinusitis (CRS) or post-traumatic olfactory dysfunction (PTOD). Briefly, subjects underwent orthonasal olfaction tests using five different odors (T&T odors) and a retronasal olfaction test using a single odor (IVO odor). The regions in the mouse olfactory bulb (OB) activated by the T&T and the IVO odors were also examined. RESULTS: Multivariate analysis of 307 cases of olfactory dysfunction (PVOD, 118 cases; CRS, 161 cases; and PTOD, 28 cases) revealed that a combination of responses to the IVO odor, but not to the T&T odors, is characteristic of PVOD, with high specificity (p < 0.001). Imaging analysis of GCaMP3 mice showed that the IVO odor selectively activated the OB region in which the axons of class I OSNs converged, whereas the T&T odors broadly activated the OB region in which axons of class I and class II OSNs converged. CONCLUSIONS: A response to T&T odors, but not IVO odor, in PVOD suggests that class I OSNs are injured preferentially, and that OSN damage in PVOD may occur heterogeneously in a neuron-type-dependent manner.