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To compare the strength of polylactide-co-glycolide fiber–reinforced calcium phosphate bone cement (FRC) with nonreinforced calcium phosphate bone cement (NRC) subjected to simulated dural pulsations in defects larger than 25 cm2.Seven NRC and 7 FRC specimens were set in both medium (37.5 cm2) and large (50.0 cm2) model skull defects while subjected to simulated dural pulsations. Specimens were removed after 24 hours and analyzed using 3-point flexural testing.All 14 FRC specimens maintained structural integrity during extraction and testing. Only 2 of 7 (29%) medium specimens and 2 of 7 (29%) large NRC specimens survived setting. The mean (SD) energy to peak force (in newton millimeters [Nmm]) of the medium and large NRC specimens was 0.88 (0.83) and 3.00 (3.54) Nmm, respectively, compared with 28.97 (16.52) and 49.91 (38.10) Nmm for the medium and large FRC specimens. The material strength (in megapascals) of the medium and large NRC specimens was 0.17 (0.15) and 0.39 (0.33) MPa, respectively, compared with 3.73 (0.99) and 2.62 (1.34) MPa for the medium and large FRC specimens. The energy to peak force and material strength of the medium and large FRC specimens were significantly greater than for the corresponding NRC specimens; results were not statistically significant between medium and large FRC specimens.Fiber-reinforced calcium phosphate bone cement exhibits superior structural integrity and material strength than NRC when subjected to unshielded simulated dural pulsations. Further studies are needed to evaluate the biophysical parameters of FRC in vivo.