NMR spectroscopy and isothermal titration calorimetry (ITC) are powerful methods to investigate ligandprotein interactions. Here, we present a versatile and sensitive fluorine NMR spectroscopic approach that exploits the 19F nucleus of 19F-labeled carbohydrates as a sensor to study glycan binding to lectins. Our approach is illustrated with the 11kDa Cyanovirin-N, a mannose binding anti-HIV lectin. Two fluoro-deoxy sugar derivatives, methyl 2-deoxy-2-fluoro--D-mannopyranosyl-(12)--D-mannopyranoside and methyl 2-deoxy-2-fluoro--D-mannopyranosyl-(12)--D-mannopyranosyl-(12)--D-mannopyranoside were utilized. Binding was studied by 19FNMR spectroscopy of the ligand and 1H15N HSQCNMR spectroscopy of the protein. The NMR data agree well with those obtained from the equivalent reciprocal and direct ITC titrations. Our study shows that the strategic design of fluorinated ligands and fluorine NMR spectroscopy for ligand screening holds great promise for easy and fast identification of glycan binding, as well as for their use in reporting structural and/or electronic perturbations that ensue upon interaction with a cognate lectin.