Ethylene glycol poisoning is a common problem and identification of ethylene glycol in serum is important for both medical and legal purposes. Other glycols like propylene glycol, 2,3-butanediol, and diethylene glycols are also abused. Common derivatization techniques to form cyclic ester of ethylene glycol work only for 1,2-diols and cannot derivatize other glycols like diethylene glycol. The authors describe novel derivatization technique of ethylene glycol (Molecular weight 62) using 4-carbethoxyhexafluorobutyryl chloride that produces a distinct protonated molecular ion peak at m/z 563 in chemical ionization mode, thus aiding in unambiguous confirmation of ethylene glycol. The authors' novel derivatization technique is not limited to 1,2-diols and can derivatize any glycol. It yields less volatile derivatives than any conventional derivatives and is free from interference from the serum matrix. Moreover, those glycols produce distinctively different mass spectra compared to ethylene glycol. Quantitation of ethylene glycol can be easily achieved by using 1,2-butanediol as an internal standard. The assay showed a within run and between run precision of 6.7% and 8.2% and a linearity from 1.1-36.1 mmol/L (70-2,240 micrograms/mliters) of serum ethylene glycol concentration.