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Many neurodegenerative diseases are related to an abnormal expansion of the CAG trinucleotide that produces polyglutamine segments in several proteins. However, the pathogenesis of these neurodegenerative states is not yet well understood. Thus, to evaluate the molecular mechanisms leading to those diseases, suitable research tools such as synthetic polyglutamine peptides are required. The synthesis and purification of such peptides are usually difficult because of poor solubility, which leads to low coupling and/or deblocking reactivity. After exploring many synthesis, solubilization and purification approaches, a protocol allowing the production of polyglutamines in good yield and high purity was developed. With this protocol, peptides of 10–30 glutamine residues were synthesized using a linear solid‐phase strategy combined with a maximal side‐chain protection scheme using fluorenylmethyloxycarbonyl (Fmoc) chemistry. After cleavage of the peptide from the polymeric support, the crude material was treated with glacial acetic acid and lyophilized. This treatment significantly improved the solubility of the polyglutamine peptides thus allowing their dissolution in aqueous conditions and purification through reverse‐phase high performance liquid chromatography. These solubilization and purification conditions led to the formation of N‐pyroglutamyl peptide derivatives that were easily isolated. These N‐pyroglutamylated compounds also appear as useful research tools because data from the literature suggest that N‐terminal modification of polyglutamine segments might play a role in their pathogenic properties. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 754–763, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com