High sensitivity biological sample measurement has been achieved by using a 10° tilted fiber Bragg grating sensing probe. Human acute leukemia cells with different intracellular densities were clearly discriminated by identifying their slight refraction index (RI) perturbations in the range from 1.3342 to 1.3344, combining with a temperature self-calibration property. We studied the relationship between the intracellular density of cells (S50 and S60) and their RIs, the experimental results provide a potential way to verify the hypothesis for "density alteration in non-physiological cells (DANCE)". The tilted fiber Bragg gratings (TFBGs) [1,2], due to the induction of a tilted angle between the UV laser beam and the fiber axis (otherwise similar to the normal straight fiber grating), provides an effective way which couples the input light from the forward-propagating core mode to backwardpropagating cladding modes [3][4][5][6]. Because of these cladding excitations, TFBG shows good sensitivity to surrounding refraction index (SRI) change [7][8][9][10][11]. With the increase of tilt angle, the envelope of the cladding-mode resonance shifts towards shorter wavelength, which shows a much improved RI sensitivity as these cladding modes propagate close to the interface between the cladding mode and the outside media. The dominant cladding modes of TFBG cover the very important region near 1.3 which can be used to measure the water and water-like solutions. Therefore, TFBGs provide a good choice for biochemical sensing. At the same time, all the wavelength resonances of a TFBG have the same temperature dependence (they shift by ~10 pm/°C), so we could only consider the relative wavelength shifts and the temperature cross sensitivity over RI measurement can be definitely eliminated [12]. In this paper, the discrimination of a group of biological samples, named S50 and S60 (corresponding to cells with different intracellular densities), which were separated from human acute leukemia cell line (K562) [13][14][15][16][17][18] by using discontinuous sucrose gradient centrifugation (DSGC) [19,20], has been achieved through a high sensitivity RI measurement by using a 10° TFBG sensing probe. By comparing the slight RI difference between S50 and S60 (ranging from 1.3343 to1.3344), we studied the relationship between the intracellular density of cells and their RI, which provide a potential way to verify the hypothesis for "density alteration in non-physiological cells (DANCE)" [21,22].