A new type of differential surface plasmon (SPR) sensor integrated with a microfluidic system is presented. The working principle of the microfluidic device is based on hydrodynamic modulation of two laminar streams inside a microchannel to provide periodic changes of the environment on the SPR sensor. The modulated reflectance is then demodulated using a lock-in amplifier. The presented sensor provides sensitivities of index of refraction about 4 × 10-8 RIU together with a 4 orders of magnitude dynamic range. This method demonstrates a sensitive detection scheme which could be used for label-free detection. © 2011 Elsevier B.V. All rights reserved.