The sensitive and specific detection of glycans via mass spectrometry (MS) remains a significant challenge due to their low abundance in complex biological mixtures, inherent lack of hydrophobicity, and suppression by other, more abundant biological molecules (proteins/peptides) or contaminants. A new strategy for the sensitive and selective MS analysis of glycans based on fluorous chemistry is reported. Glycan reducing ends were derivatized with a hydrophobic fluorinated carbon tag, increasing glycan ionization efficiency during MS by more than an order of magnitude. More importantly, the fluorinated carbon tag enabled efficient fluorous solid-phase extraction (FSPE) to specifically enrich the glycans from contaminated solutions and protein mixtures. Finally, we successfully analyzed the N-glycome in human serum using this new method.