The first structure of a human β-galactoside α-2,6-sialyltransferase I was determined by SIRAS phasing using an iodide soak for derivatization. An elongated glycan from a crystallographic neighbour binds to the active site, mimicking a substrate complex. An analysis of the substrate interactions and a comparison with other sialyltransferases allowed the modelling of a Michaelis complex and conclusions on the catalytic mechanism.