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Two-dimensional (2D) MoS2 with appealing physical properties is a promising candidate for next-generation electronic and optoelectronic devices, where the ultrathin MoS2 is usually laid on or gated by a dielectric oxide layer. The oxide/MoS2 interfaces widely existing in these devices have significant impacts on the carrier transport of the MoS2 channel by diverse interface interactions. Artificial design of the oxide/MoS2 interfaces would provide an effective way to break through the performance limit of the 2D devices but has yet been well explored. Here, we report a high-performance MoS2-based phototransistor with an enhanced photoresponse by interfacing few-layer MoS2 with an ultrathin TiO2 layer. The TiO2 is deposited on MoS2 through the oxidation of an e-beam-evaporated ultrathin Ti layer. Upon a visible-light illumination, the fabricated TiO2/MoS2 phototransistor exhibits a responsivity of up to 2,199 A/W at a gate voltage of 60 V and a detectivity of up to 1.67 × 1013 Jones at a zero-gate voltage under a power density of 23.2 μW/mm2. These values are 4.0 and 4.2 times those of the pure MoS2 phototransistor. The significantly enhanced photoresponse of TiO2/MoS2 device can be attributed to both interface charge transfer and photogating effects. Our results not only provide valuable insights into the interactions at TiO2/MoS2 interface, but also may inspire new approach to develop other novel optoelectronic devices based on 2D layered materials.