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A CMOS Active Column Sensor (ACS) with FPN noise reduction is developed for Surface Plasmon Resonance (SPR) biosensing applications. For a SPR interface where the materials are compatible with a post-CMOS fabrication process a 68° coupling angle and a reflectance change of 75% are obtained. Furthermore, these materials provide the possibility of integration with the rest of the elements in an SPR biosensor in a single chip, including a CMOS ACS for the photodetection stage. The 20 × 20 μm2 pixel uses a n-well/p-sub photodiode, three transistors (3T) configuration, with a 61% fill factor and 5.2 μV/e- conversion gain. Non Correlated Double sampling (NCDS) and double delta sampling (DDS) schemes are implemented for noise handling, where a Monte Carlo analysis shows a reduction of the output's variance.