High-temperature tension-compression fatigue behavior of polymer matrix composites with a 2D and a 3D fiber architecture was examined. The two composites studied in this work have the same NRPE polyimide matrix and carbon fiber reinforcement, but different fiber architectures. The 3D composite is a single-ply non-crimp 3D orthogonal weave material whereas the 2D laminated composite contains fifteen 0/90 woven plies. The study aims to evaluate the fitness of the two materials for service in aerospace thermal-protection systems. Thus mechanical testing was conducted under environmental conditions mimicking the realistic service environment: one side of the test specimen was held at 329 °C whilst the other side remained open to ambient laboratory air. The tension and compression stress-strain responses of the two composites were investigated and the basic tensile and compressive properties measured. The high-temperature properties were similar to those obtained at room temperature. Fully-reversed tension-compression cyclic tests were carried out at elevated temperature. The frequency was 1.0 Hz, the ratio of minimum to maximum stress was −1.0, and the runout condition was defined as survival of 200,000 cycles. The evolution of maximum and minimum strains with cycles as well as the progressive change in modulus were examined for each test. The 3D composite produced a higher fatigue limit, while the 2D laminated composite displayed a slightly better fatigue performance at higher stress levels. All specimens that survived 200,000 cycles without failure were tested in tension to failure to assess the retained tensile strength and stiffness. Examination of tested specimens with an optical microscope showed extensive delamination of the 2D composite. The 3D composite proffered enhanced delamination resistance.