Summary Tat is regarded as an attractive target for the development of an AIDS vaccine. However, works suggest that Tat is a poorly immunogenic protein and therefore we attempted to increase its immunogenic potency. As we observed that Tat is highly sensitive to enzymatic degradation in vitro we tried to make it less susceptible to proteolysis using ligands. We complexed Tat101 with various sulfated sugars and observed that some of these ligands made the protein more resistant to proteolysis and more immunogenic. In a more thorough study, we observed that a low-molecular-weight heparin fragment, called Hep6000, altered both the cell-binding capacity and transactivating activity of Tat101, suggesting that this sulfated polysaccharide can make the protein less toxic. Sera raised against Tat101 and Tat101/Hep6000 similarly bound mainly to the N-terminal region of the protein, indicating that formation of the complex does not alter the B-cell immunodominant region. Anti-Tat101/Hep6000 antisera neutralized the transactivating activity of Tat101 more efficiently than anti-Tat101 antisera. Altogether, these results indicate that stabilization of Tat101 using sulfated sugars increases its immunogenicity and might be of value in increasing its vaccine efficacy.