Serum amyloid A (SAA), a small lipophilic plasma protein elevated in inflammation, is a precursor of amyloid A (AA) amyloidosis, the major life-threatening complication of chronic inflammation in animals and humans. Although heparan sulfate (HS) is a potent amyloid agonist, particularly in AA amyloidosis, therapeutic targeting of SAA-HS interactions using a small-molecule HS/heparin decoy was unsuccessful. To understand molecular underpinnings, we used recombinant lipid-free human and murine SAA1 and human SAA2 to explore their interactions with various glycosaminoglycans at pH 5.5-7.4 during amyloid formation, from native protein to amyloid oligomers and fibrils. Effects of pH and glycosaminoglycan sulfation/charge supported by prior computational studies indicate electrostatic origin of SAA-glycosaminoglycan interactions. HS/heparin can promote amyloidogenesis by inducing non-native β -sheet and apparently causing liquid droplet formation in SAA in solution. Structural and binding studies by spectroscopy and ELISA reveal previously unknown synergy between amyloid formation and heparin/HS binding by SAA. We propose that this synergy potentially extends to other protein amyloids and stems from longitudinal binding of HS polyanions to basic residue arrays on amyloid oligomers or fibrils. This binding mode explains our finding that a minimal heparin chain length exceeding 20 monosaccharides is necessary to compete with HS for binding to amyloid oligomers. The results help explain prior failure of a small-molecule drug in targeting of SAA-HS interactions and consider alternative HS-targeting approaches for AA and, potentially, other amyloid diseases.