Purpose: This study aimed to evaluate the probability of survival, Weibull modulus, characteristic strength, and failure modes of computer-aided design/computer-assisted manufacture (CAD/CAM) fiber-reinforced composite (FRC) substructures used for implant-supported fixed dental prostheses (ISFDPs). Materials and Methods: Three-unit ISFDPs (first molar pontic) fabricated as a monolithic composite piece or as composite veneered on a CAD/CAM FRC substructure with either a 12-mm2 or 3-mm2 connector area (n = 18 each) were subjected to step-stress accelerated life testing in water. Use-level probability Weibull curves and the probability of survival were calculated. Fractographic analysis was performed under polarized light and scanning electron microscopy. Results: Fatigue did not accelerate the failure of any group, whereas prosthesis strength was the main factor in increased failure (β 1). The probability Weibull contour plot showed no differences between the ISFDPs with 12 mm2 and the monolithic composite ISFDP in characteristic strength (η = 643.5 N and 742.7 N, respectively) or Weibull modulus (6.7 and 5.8, respectively), whereas both were significantly higher than 3 mm2 (444.91 N and 9.57). The probability of survival was not statistically different between groups at 100,000 mission cycles at 300 N. Differences were observed in fatigue failures above 800 N; monolithic composite ISFDPs failed catastrophically, whereas those with CAD/CAM FRC substructures presented veneer/composite cohesive or adhesive failures. Cracks evolved from the occlusal contact toward the margins of the cohesively failed composite, and in CAD/CAM FRC prostheses, competing failure modes of cracks developing at the connector area with those at the indentation contact were observed. Conclusion: The probability of survival did not differ between CAD/CAM FRC with either 3-mm2 or 12-mm2 connector areas, monolithic composite, or metal-ceramic ISFDPs previously tested under the same methodology. However, differences in failure modes were detected between groups. Keywords: computer-aided design/computer-assisted manufacture, fiber-reinforced composite, fixed dental prostheses, fatigue, Weibull