The aim of the present study was to investigate the influence of five different preparation designs and two different ceramic thicknesses on margin quality and fracture resistance of ceramic laminate veneers after thermomechanical loading in vitro. Eighty human central incisors were randomly assigned to 10 groups (n = 8) with five different preparation designs: non-prep (NP), minimally invasive (MI) = exclusively enamel-bonded, semi-invasive (SI) = 50% bonded in dentin, invasive (I) = 100% in dentin, and semi-invasive with two additional class III composite resin restorations (SI-C). IPS InLine veneers were fabricated in two thicknesses (L1 = 0.2-0.5mm; L2 = 0.5-1.2mm). After adhesive luting (OptiBond FL, Variolink Veneer) with light curing and polishing, specimens were stored in distilled water at 37°C for 21days, then thermocycled (2000 cycles between + 5 and + 55°C), and finally mechanically loaded at the incisal edge at an angle of 45° for 2,000,000 cycles at 50N und further 1,000,000 cycles at 100N. Impressions were taken initially, after thermocycling, and after every 250,000 mechanical cycles in order to evaluate cracks and margin quality under a SEM. The veneers were evaluated in a light microscope (× 20) for cracks, chippings, partial, and catastrophic fractures. Margin quality after three million cycles revealed medians for continuous margin of 82-95% without significant differences among groups, neither at the ceramic/composite (p = 0.943) nor at the tooth/composite interface (p = 0.571). Visual inspection of veneers exhibited 22 cracks, 11 chippings, 4 partial and 4 catastrophic fractures in 38 of 80 veneers. The statistical ranking regarding fracture risk (p ≤ 0.05) was: IL1 = SIL1 = MIL1 = IL2 = CL1 = CL2, MIL2 = NPL1 = NPL2 = SIL2, IL2 = CL1 = CL2 = MIL2 = NPL1 = NPL2 = SIL2. Even after three million cycles with up to 100N, all groups showed high survival rates. However, the fracture risk increases with thin veneers and preparations with medium to high dentin portions when compared to thicker veneers with preparations in enamel or partially in dentin (p ≤ 0.05). Preexisting resin composite restorations did not show any significant influence on margin quality and facture risk (p > 0.05). Ceramic laminate veneers are extremely durable with thin veneers and substantial enamel loss being main risk factors for fracture.