We prepared segmented poly(urethane-urea)s (SPUUs) from a lysine-based diisocyanate (LDI) and an aliphatic polyester poly(ε-caprolactone) diol (PCL-diol), and 1,4-butanediamine (BDA). We also investigated the molecular aggregation structure, mechanical performance and biodegradability. Differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), Fourier transform infrared spectroscopy (FT-IR), wide-angle X-ray diffraction (WAXD) and small-angle X-ray scattering (SAXS) measurements indicated that the LDI-based hard segment (HS) shows weak segregation because of the bulky asymmetric chemical structure of the LDI. The stress-strain curve of PCL(1250)-LDI-BDA exhibits a yielding point and less mechanical strength than PCL(1250)-BDI-BDA because of the plastic deformation of the HS domains. PCL(1250)-LDI-BDA shows adequate biodegradability due to weak aggregation capacity of LDI-based components.