Purpose: To analyze the effect of material thickness on the fatigue behavior and failure load of monolithic polymer-infiltrated-ceramic-network (PICN) computer-aided design/computer-assisted manufacture (CAD/ CAM) crowns. Materials and Methods: PICN (VITA Enamic) molar crowns with standard (PICN-ST, 1.5 mm) and reduced (PICN-RED, 1.0 mm) thicknesses were investigated (n = 28). Monolithic zirconia (Z-ST, InCoris TZI) served as control. Failure loads before and after fatigue (1.2 million cycles, 198 N) were evaluated. Data were analyzed pairwise using Wilcoxon rank sum test, and resulting P values were adjusted using the Bonferroni-Holm method, with P .05 considered significant and a prior power analysis. Results: All crowns survived fatigue. Mean failure loads before and after fatigue (respectively) were as follows: PICN-ST: 1,889 ± 341 N and 2,547 ± 876 N; PICN-RED: 2,119 ± 338 N and 2,367 ± 719 N; and Z-ST 5,141 ± 1,194 N and 2,531 ± 682 N. Conclusion: PICN with a reduced thickness of 1 mm appeared to be a reliable CAD/ CAM material for posterior crowns.