We demonstrate an approach for highly sensitive bio-detection based on silicon nanowire field-effect transistors by employing low frequency noise spectroscopy analysis. The inverse of noise amplitude of the device exhibits an enhanced gate coupling effect in strong inversion regime when measured in buffer solution than that in air. The approach was further validated by the detection of cardiac troponin I of 0.23 ng/ml in fetal bovine serum, in which 2 orders of change in noise amplitude was characterized. The selectivity of the proposed approach was also assessed by the addition of 10 μg/ml bovine serum albumin solution.