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We present a periodically segmented waveguide Fabry-Pe´rot interferometer (PSW-FPI) intended to be used for tagless real-time chemical/ biological sensing through bulk-material interaction. The differential sensor detects changes in the refractive index (RI) of a sample regardless of its absolute RI value. Experiments with a series of sucrose solutions of various concentrations are compared with theoretical results, and a very good match is found between the two. The theoretical sensitivity limit for a 50-dB-signal-to-noise-ratio (SNR) measurement system is estimated as δn=3·10-7. For a 29-dB-SNR measurement system, a measured sensitivity limit of δn=4·10-5 is comparable with the previously reported sensitivities of label-free real-time optical biosensors (2·10-5-5·10-5). However, the total required sensing length (720 μm) of our PSW-FPI sensor is much shorter than that of the previously reported devices (9-20 mm).