We describe a straightforward synthetic strategy for a new family of functional poly(ester-amide)s (PEAs) with tertiary ester linkages via the Passerini multicomponent polymerization (Passerini-MCP) of a diacid (A2), 1,6-diisocyanohexane (B2), and four kinds of electron-deficient ketones. First, Passerini three-component reactions (Passerni-3CR) of hexanoic acid and tert-butyl isocyanide with nine kinds of ketones were investigated to evaluate the reactivities of these ketones toward Passerni-3CR. Four electron-deficient ketones, 1,1,1-trifluoroacetone (1), 1,1,1-trifluoroacetophenone (2), ethyl pyruvate (3), and 2,3-butanedione (4), were found to be excellent oxo-compounds for this Passerini-3CR. Then, the Passerini-MCP of A2 and B2 with 1, 2, 3, and 4 in CH2Cl2 was performed to generate polymers P1-P4 with tertiary ester linkages and different electron-withdrawing substituents. Polymer P5 was also prepared by the Passerini-MCP of A2 and B2 with phenylacetaldehyde (5) for comparison. Size exclusion chromatography (SEC) verified the high molecular weights (Mn up to 30.6 kDa) of these polymers. The structures of these polymers were confirmed by H-1 NMR, C-13 NMR, F-19 NMR, and matrix-assisted laser desorption ionization mass spectroscopy. Thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) revealed that P1P4 are less stable than polymer P5, and they are amorphous with variable glass transition temperatures (T-g) depending on the side groups. Hydrolytic degradation of P1, P4, and P5 in a mixture of acetonitrile and phosphate buffer (different pH) was investigated, and at the same pH, the degradation follows the order of P4 > P1 > P5. The static water contact angles of thin films formed by these polymers decreased from 96 degrees (P1) to 78 degrees (P2), 50 degrees (P3), and finally to 32 degrees (P4). Tensile properties of polymer P3 and P4 were characterized by dynamic mechanical analysis (DMA). P4 displayed a high tensile stress of 25 MPa with the elongation up to 200%.