Conformational analysis of two alternating copolymers, poly(ethylene imine-alt-ethylene oxide) (PEIEO) and poly(N-methylethylene imine-alt-ethylene oxide) (PMEIEO), has been carried out by the inversionalrotational isomeric state (IRIS) analysis of ab initio molecular orbital (MO) calculations and 1 H and 13 C NMR experiments for their model compounds. On the basis of the conformational energies derived therefrom and molecular mechanics and MO calculations, higher-order structures, physical properties, and functions of the two copolymers have been predicted as an example of molecular design. These copolymers are expected to form various hydrogen bonds: PEIEO, N-H‚‚‚O (interaction energy, -1.75 kcal mol -1 ), C-H‚‚‚N (-0.68 kcal mol -1 ), and C-H‚‚‚O (-0.21 kcal mol -1 ); PMEIEO, C-H‚‚‚N (-0.66 kcal mol -1 ), and C-H‚‚‚O (-0.41 kcal mol -1 ). In particular, the N-H‚‚‚O hydrogen bond of PEIEO is too strong to be broken even by protic solvents such as methanol and water but replaced by an intermolecular N-H‚‚‚OdS attraction in dimethyl sulfoxide. The C-N and C-O bonds of PEIEO prefer the trans state as found for poly(ethylene imine) (PEI) and poly-(ethylene oxide), whereas the C-C bond does not have its own conformational preference and its conformational equilibrium is determined only by the hydrogen bond strength (HBS). The characteristic ratio of PEIEO largely depends on HBS: 1.5 (HBS ) 100%); 6.5 (0%). In contrast, the weak hydrogen bonds of PMEIEO little affect the characteristic ratio; 5.2 (HBS ) 100%); 5.9 (0%). According to Mattice's analysis (Macromolecules 2004, 37, 4711), PEIEO and PEI tend to form circular paths due to the intramolecular hydrogen bonds. Both molecular mechanics calculations using the Amber force field and density functional MO calculations under the periodic boundary condition have suggested that a double-helical structure may be formed in the PEIEO crystal. The possibility that these copolymers will be utilized as gene carriers and ion conductors is discussed, and the synthetic method is also suggested. In conclusion, these copolymers should be promising and deserve to be synthesized.