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This paper discusses the optimization of a stretchable electrical interconnection between integrated circuits in terms of stretchability and fatigue lifetime. The interconnection is based on Cu stripes embedded in a polyimide-enhanced (PI-enhanced) layer. Design-of-experiment (DOE) methods and finite-element modeling were used to obtain an optimal design and to define design guidelines, concerning both stripe and layer dimensions and material selection. Stretchable interconnects with a PI-enhanced layer were fabricated based on the optimized design parameters and tested. In situ experimental observations did validate the optimal design. Statistical analysis indicated that the PI width plays the most important role among the different design parameters. By increasing the PI width, the plastic strain in the Cu stripes is reduced, and thus, the stretchability and fatigue lifetime of the system is increased. The experimental results demonstrate that the PI-enhanced stretchable interconnect enables elongations up to 250% without Cu rupture. This maximum elongation is two times larger than the one in samples without PI enhancement . Moreover, the fatigue life at 30% elongation is 470 times higher.