Large infrastructure systems (e.g., transportation networks) cannot be designed and operated based only on standard regulations provided by codes of practice and operations manuals. It is necessary to consider not only safety and functionality, but also the socioeconomic context and the cost effectiveness of an investment throughout its life cycle. This paper presents a model to optimize both the design parameters and the inspection and maintenance policies by maximizing the net present value of a project. The model uses decision trees and simulation methods, which take into account the uncertainties and variability in the mechanical performance of the system and in the decision process. The proposed model is illustrated using both a single structure and an entire transportation network located in a seismic region. The results present the variability of the design parameters and the inspection policies within several seismic environments and life cycles of a project. They also show that structural and operational optimization along with the appropriate contextual restrictions (e.g., financial, length of life cycle), are significant for the management of existing systems as well as the development of future infrastructure systems.