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To improve the sensitivity of seawater refractive index (RI) measurement, fluorine-doped fiber (FDF)-sandwiched Mach–Zehnder interferometer (MZI) is proposed, which is fabricated by splicing a short section of FDF between two sections of single-mode fibers (SMFs) with a large lateral offset. In FDF-sandwiched MZI, the two light paths are the FDF cladding and the measured seawater. The FDF cladding has lower RI than that of normal single-mode fiber (SMF), so the FDF-sandwiched MZI has higher sensitivity than that of SMF-sandwiched MZI. The results show that the RI sensitivity of the proposed sensor can be up to −14,638 nm/RIU, which is about 10.9% higher than that of SMF-sandwiched MZI. Temperature cross-sensitivity of our sensor is only 1.7 × 10−6 RIU/°C. The proposed sensor has the potential application in real physical, chemical, and biological sensing. [ABSTRACT FROM AUTHOR]