Photoconductivities of monocrystalline vanadium pentoxide (V2O5) nanowires (NWs) with layered orthorhombic structure grown by physical vapor deposition (PVD) have been investigated from the points of view of device and material. Optimal responsivity and gain for single-NW photodetector are at 7,900 A W-1 and 30,000, respectively. Intrinsic photoconduction (PC) efficiency (i.e., normalized gain) of the PVD-grown V2O5 NWs is two orders of magnitude higher than that of the V2O5 counterpart prepared by hydrothermal approach. In addition, bulk and surface-controlled PC mechanisms have been observed respectively by above- and below-bandgap excitations. The coexistence of hole trapping and oxygen sensitization effects in this layered V2O5 nanostructure is proposed, which is different from conventional metal oxide systems, such as ZnO, SnO2, TiO2, and WO3.