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Alternating polypeptoids are particularly appealing because alternating sequence may impart highly ordered structure and special functions, while their simple synthesis still remains a key challenge. We describe that natural amino acid monomers can be polymerized via Ugi reaction in a step-growth fashion as an AA′ BB′ system, which leads to alternating polypeptoids with molecular weight up to 15 kg/mol. These alternating polypeptoids are thermally responsive and exhibit cloud points (Tcp) between 27 and 37 °C. Importantly, the marriage of high functionality of amino acids with Ugi reaction also enables the preparation of polypeptoids encoding both protected amino and carboxyl groups in the side chains with alternating arrangement. The cleavage of the protecting groups leads to alternating polyampholytes without any compositional drift. Such alternating polyampholytes not only exhibit high water solubility (>100 mg/mL) but also demonstrate the ability to resist aggregation with proteins. Moreover, the cell viability measurements reveal that these materials have minimal cytotoxicity to HeLa cells. Overall, this study offers us a simple way to prepare a variety of polypeptoids and polyampholytes as new protein-resistant materials for bioapplications.