Noninvasive monitoring of blood glucose concentration in diabetic patients would significantly reduce complications and mortality associated with this disease. In this paper, we experimentally and theoretically studied specificity of noninvasive blood glucose monitoring with the optical coherence tomography (OCT) technique. OCT images and signals were obtained from skin of Yucatan micropigs and New Zealand rabbits. Obtained results demonstrate that: (1) several body osmolytes may change the refractive index mismatch between the interstitial fluid (ISF) and scattering centres in tissue, however the effect of the glucose is approximately one to two orders of magnitude higher; (2) an increase of the ISF glucose concentration in the physiological range (3–30 mM) may decrease the scattering coefficient by 0.22% mM⁻¹ due to cell volume change; (3) stability of the OCT signal slope is dependent on tissue heterogeneity and motion artefacts; and (4) moderate skin temperature fluctuations (±1 °C) do not decrease accuracy and specificity of the OCT-based glucose sensor, however substantial skin heating or cooling (several °C) significantly change the OCT signal slope. These results suggest that the OCT technique may provide blood glucose concentration monitoring with sufficient specificity under normal physiological conditions.