This paper reports a device that performs nanoparticle detection with a microfluidic differential Resistive Pulse Sensor (RPS). By using a single microfluidic channel with two detecting arm channels placed at the two ends of the sensing section, the microfluidic differential RPS can achieve a high sensitivity allowing the detection of nanometer size particles. Two-stage differential amplification is used to further increase the signal-to-noise ratio. This method is able to detect nanoparticles of 490nm on a microfluidic chip. An 8μm gate and a 2.7μm gate detected the 490 nm particle. The electrical signal was with optical evidence. The result showed 2.7μm chip can realize signal to noise ratio higher than 10. The method described in this paper is simple and can be applied to develop a compact device without the need of bulky, sophisticated electronic instruments or complicated nano-fabrication processes.© (2010) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.