Abstract: Optical fiber surface plasmon resonance (SPR) sensor combines the advantages of optical fiber sensor like miniaturization, online transmission, easy operation and SPR biodetection technology, which is highly sensitive, highly selective and label-free. It is currently a research hotspot of immunological biosensors. However, the signal of traditional multi-mode fiber based SPR sensor is easy to be lost and distorted in long-distance transmission. In this paper, a single mode-no core-single mode fiber based SPR sensor was proposed, which could effectively reduce the loss and distortion in signal transmission, and was suitable for connecting with the current optical fiber network. In order to eliminate the interference signal in the sensor, the core diameter of the no core fiber was changed, the methods of removing background interference and Gaussian fitting were adopted, and finally the sensor with the sensing region of 61.5 μm no core fiber was selected, the effective SPR spectrum signal was extracted from it. The sensitivity of proposed sensor is 1153.40 nm/RIU and the resolution is 1.70×10⁻⁴ RIU. The successful development of this kind of optical fiber biosensor provides a new idea for intelligent medical treatment and telemedicine.