Structural health monitoring is recognized as a viable solution to increase aviation safety and decrease operating costs enabling a novel maintenance approach based on the actual condition of the airframe, mitigating operating costs induced by scheduled inspections. However, the net benefit is hardly demonstrated, and it is still unclear how the implementation of such an autonomic system can affect performance at aircraft level. To close this gap, this paper presents a systematic analysis where the impact of cost and weight of integrating permanently attached sensors—used for diagnostics- affect the main performance of the aircraft. Through a multidisciplinary aircraft analysis framework, the increment of aircraft operating empty weight is compared with the possible benefits in terms of direct operating costs to identify a breakeven point. Furthermore, the analysis allows to establish a design guideline for structural health monitoring systems returning a safer aircraft without any economic penalties. The results show that the operating costs are lower than those of the reference aircraft up to 4% increase in maximum take-off weight. Paper findings suggest to considering a condition monitoring strategy from the conceptual design stage, since it could maximize the impact of such innovative technology. However, it involves in a design of a brand-new aircraft instead of a modification of an existing one.