Background <p>This in-vitro study was planned to evaluate the fracture load of translucent zirconia overlay restoration made with different tooth preparation designs.</p> Materials and methods <p>Thirty-two sound mandibular molars were divided into four main groups (<i>n</i> = 8), based on different overlay preparation designs. Group 1 anatomic cusps with chamfer finish line (ACC), group 2: flat cusp with chamfer finish line (FCC), group 3: anatomic cusp reduction with proximal steps (ACS), group 4: flat cups reduction with proximal steps (FCS). The teeth were restored using translucent monolithic zirconia (IPS e.max ZirCAD, Ivoclar, FL). Cementation was performed using adhesive resin cement. Specimens were stored in water at 37&#xa0;°C for 45 days then followed by cyclic loading fatigue for 120,000 cycles. Finally, specimens were fractured under compressive load in Newton (N) using a universal testing machine. A stereo microscope and scanning electron microscope (SEM) were used to examine and categorize the failure pattern modes. Two and one-way ANOVAs and Post hoc Tukey tests were used for statistical analyses.</p> Results <p>Group ACC demonstrated the highest fracture resistance (4371 ± 440), followed by ACS group (3995 ± 274) and FCC group (3954 ± 698), FCS group showed the lowest fracture load (3483 ± 567).</p> Conclusion <p>Both cusp design and margin design affected fracture resistance. Anatomical cusp with chamfer finish line showed the highest fracture resistance.</p>