Objective: To analyze the influence of restoration design (partial-coverage restoration vs. crown) and ceramic layer thickness on the performance and failure loads of CAD/CAM-fabricated lithium disilicate (LDS) reconstructions on molars after fatigue. Materials and Methods: Seventy-two posterior monolithic CAD/CAM-fabricated LDS restorations (IPS e.max CAD, Ivoclar Vivadent) with different occlusal/buccal ceramic layer thicknesses (1.5/0.8, 1.0/0.6, and 0.5/0.4 mm) and restoration designs (PCR: non-retentive full-veneer/partial-coverage restoration, C: crown,) were investigated and divided into six groups (n = 12, test: PCR-1.5, PCR-1.0, PCR-0.5; control: C-1.5, C-1.0, C-0.5). LDS restorations were adhesively bonded (Variolink Esthetic DC, Ivoclar Vivadent) to dentin-analogue composite dies (Z100, 3M ESPE). All specimens were subjected to thermomechanical loading (1.2 million cycles, 49 N, 1.6 Hz, 5–55°C) and exposed to single load to failure testing. Failure analysis was performed with light and scanning electron microscopies. Data were statistically analyzed using ANOVA, Tukey-Test, and t-test (p < 0.05). Results: Eight crown samples (C-0.5) and one PCR specimen (PCR-0.5) revealed cracks after fatigue, resulting in an overall success rate of 87.5% (crowns: 75%, PCRs: 96.88%). Direct comparisons of PCRs versus crowns for thicknesses of 0.5 mm (p < 0.001) and 1.0 mm (p = 0.004) were significant and in favor of PCRs. Minimally invasive PCRs (0.5 and 1.0 mm) outperformed crowns with the identical ceramic thickness. No difference was detected (p = 0.276) between thickness 1.5 mm PCRs and crowns. Conclusions: Minimally invasive monolithic CAD/CAM-fabricated posterior LDS PCRs (0.5 and 1.0 mm) resulted in superior failure load values compared to minimally invasive crowns. Minimally invasive crowns (0.5 mm) are prone to cracks after fatigue. Clinical Significance: Minimally invasive CAD/CAM-fabricated LDS PCR restorations with a non-retentive preparation design should be considered over single crowns for molar rehabilitation. © 2023 The Authors. Journal of Esthetic and Restorative Dentistry published by Wiley Periodicals LLC.