We have described here the development of a glycomimetic ligand, Man84; that exclusively binds to L-SIGN with affinity in the low µM range and barely interacts with DC-SIGN. The Compound selectivity has been established by several biophysical methods at the molecular and cellular level, demonstrating the viability of the tool. A structural characterization of the L-SIGN CRD/Man84 complex allowed to determine that the origin of this selectivity lies mainly in the presence of a triazoleguanidine group, which introduces both steric and electrostatic complementarity with the L-SIGN active site, while producing unfavorable interactions in the corresponding site of DC-SIGN. To the best of our knowledge, this level of selectivity is unprecedented for glycomimetic structures targeting CLRs with similar specifity and is particularly striking because the CRDs of DC-SIGN and L-SIGN share 72% of their primary structure. On the other hand, X-ray analysis of the Man84/L-SIGN complex and comparison with the same region of DC-SIGN allows to locate the origin of the selectivity in a single aminoacid difference (Asn385 in L-SIGN vs. Lys373 in DC-SIGN). This reinforces the notion that rational differential design that we have used in a different context to obtain selectivity towards DC-SIGN and against langerin 46 can be a powerful tool towards selective lectin ligands.