The invention provides methods for the PEGylation of an N-terminal cysteine of a polypeptide such that the thiol group of the cysteine is unreacted in the fmal PEGylated polypeptide. In one embodiment, the invention comprises a method of PEGylating a polypeptide having an N-terminal cysteine, the method comprising: contacting the polypeptide with a polyethylene glycol (PEG) derivative having a free aldehyde group in a reaction mixture under reducing conditions such that the N-terminal cysteine in the resultant PEGylated polypeptide has a free thiol group.
