BSA can form amyloid-like aggregates in vitro at 65 °C. Heterologous amyloid can proposedly cross-seed other protein's aggregation, however, general mechanisms and driving conditions remain to be vividly elucidated. Here, we examined if pre-formed HEWL amyloid can cross-seed the aggregation of BSA at physiological temperature, 37 °C, and whether the efficacy depends on the BSA conformation. We find that at pH 3.0, 37 °C where BSA manifests exposure of abundant hydrophobic patches, HEWL amyloid efficiently drives BSA into ThT-positive, sarkosyl-resistant, β-sheet rich amyloid-like aggregates exhibiting fibrils in TEM. On the contrary, HEWL amyloid fails to cross-seed the BSA aggregation at pH 7.0, 37 °C where BSA has largely internalized hydrophobic patches. Strikingly, human lysozyme amyloid could also cross-seed human serum albumin aggregation at pH 3.0, 37 °C. Thus, heterologous amyloid cross-seeding can help overcome the energy-barrier for aggregation of other proteins that, for any reason, may have perturbed and promiscuous structural conformation at physiological temperatures. © 2021 Elsevier B.V.