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This paper presents a fully integrated hardware solution to processing signals obtained from biochemical sensors that employ surface plasmon resonance (SPR)-based transduction mechanisms. Results are discussed in the context of previous software-based, partial hardware-based, and alternative fully hardware-based solutions for portable SPR systems. As in previous alternative design approaches, this system-on-chip solution is tested in the context of a highly portable sensing configuration consisting of a fiber-based optical path and LED-based light source using a nonfunctionalized SPR probe. The results are applicable to both functionalized (analyte-specific) and nonfunctionalized (bulk refractive index) sensing systems. The output of the chip is an optimized single voltage that represents the refractive index of the sensing environment. The single-chip solution is a novel combination of a photodiode, a photodiode biasing scheme, current-mode dark current/fixed pattern noise compensation, programmable current-mode background (reference) compensation, and an integration stage for weighting signals from multiple wavelengths to compute a single voltage output. Experimental results, including the effects of electronic noise, batch mismatch, and quantization error demonstrate a 6.8 resolution in refractive index units. This result is markedly improved over previous fully integrated solutions (3 resolution), and is comparable to traditional-software solutions (5 resolution) to SPR-based sensing problems.