A new process for the preparation of large amounts of thioated oligonucleotides in a quasi-classical solution condition is described. This method takes advantage of the use of polyethylene glycol as a soluble, inert support during synthesis. The easy purification of intermediates from a moderate excess of reagents allows very high coupling yields and, consequently, efficient production of the long oligonucleotide sequences required for pharmacological applications. The reaction of properly protected and activated oligonucleotides with high-molecular-weight polyethylene glycols allows a convenient procedure for the postsynthetic conjugation of those biopolymers in solution. The oligonucleotides are modified at the 5' terminus using a liquid-phase procedure with a linker carrying a terminal primary amino group to enhance its nucleophilic reactivity. The use of N, N'-disuccinimidyl carbonate for the activation of the terminal OH groups of the PEG was preferred.