Huntington's disease and six other neurodegenerative diseases are associated with abnormal gene products containing expanded polyglutamine (poly‐Q; Q_n) domains (n ≥ 40). In the present work, we show that glutathione S‐transferase (GST) fusion proteins containing a small, physiological‐length poly‐Q domain (GSTQ₁₀) or a large, pathological‐length poly‐Q domain (GSTQ₆₂) are excellent substrates of guinea pig liver (tissue) transglutaminase and that both GSTQ₁₀ and GSTQ₆₂ are activators of tissue transglutaminase‐catalyzed hydroxaminolysis of N‐α‐carbobenzoxyglutaminylglycine. The present findings have implications for understanding the pathophysiological mechanisms of expanded CAG/poly‐Q domain diseases.