AbstractPolyurethane grouting technology has been applied in the maintenance and reinforcement of transportation infrastructure such as airports, expressways, and high-speed railways. For rigid pavements with voids underneath concrete slabs, it can make a quick and efficient fix. However, polyurethane grouting materials applied underneath slabs for base enhancement are subjected to cyclic compressive loading from traffic, so their fatigue performance is critical in the concrete–polyurethane composite structure. There have not been many studies of this aspect. This paper investigated the influence of several key design factors, including grout thickness, grout density, and void shape, on the stress–strain and fatigue performance of the concrete–polyurethane composite structure. Laboratory compressive tests were conducted at various stress levels following a four-factor, three-level orthogonal experiment design. The results showed that the strain response of composite specimens under stress-controlled cyclic loading may be divided into three stages: an initial stage in which the cumulative strain changes little with the number of load repetitions, a second stage in which the cumulative strain increases steadily with the number of load repetitions, and a third stage in which the cumulative strain increases rapidly with the number of load repetitions. The third stage represents the occurrence of fatigue failure. The rank of the influences of the four factors on fatigue performance is, from high to low, grout thickness, stress ratio, void shape, and grout density.