Abstract Serum amyloid A (SAA) is a small apolipoprotein that binds to high-density lipoproteins (HDLs) via its N-terminus. The murine isoform SAA2.2 forms a hexamer in solution and the N-terminus is shielded from the solvent. Therefore, it is unclear how the SAA2.2 hexamer might bind HDL. In this study, the binding of SAA2.2 to murine HDL was investigated by glutaraldehyde cross-linking and polyacrylamide gel electrophoresis. The hexamer did not bind HDL significantly at 20 °C. However, at temperatures between 25–30 °C, SAA2.2 became destabilized and its monomeric form bound to HDL. SAA2.2 binding did not significantly replace Apo A-I in HDL particles. At 37–45 °C SAA2.2 binds less to HDL, suggesting that its binding is weak and sensitive to physiological and pathological temperatures, and thereby, potentially modulated, in vivo, by other factors.