Statement of the problem: Conservative esthetic restorative dentistry has become an essential component in modern clinical practice. However, the inlay retained fixed partial dentures (IRFPDs) have a higher risk of fracture and dislodgement due to minimal preparations. Purpose: to compare fracture resistance and retention of Lithium disilicate (IPS e.max) and Polyetheretherketone (BioHPP) IRFPDs fabricated with heat-press technique and CAD/CAM system. Materials and Methods: Forty models, each including extracted mandibular 2 nd premolar and 2 nd molar embedded in an epoxy resin block with 10 mm intra-abutment distance representing missing mandibular 1 st molar were constructed. The premolar and molar of each model received standardized class II inlay preparations. The constructed models were randomly divided into four groups; Group (1): IPS e.max Press IRFPDs, Group (2): IPS e.max CAD IRFPDs, Group (3): BioHPP Granulates IRFPDs, and Group (4): breCAM.BioHPP IRFPDs. All IRFPDs were cemented using RelyX Ultimate adhesive resin cement. Samples were stored for 24 hours in distilled water at 37°C, and then thermocycled for 5000 cycles. Universal testing machine was used to measure fracture and dislodging loads. Samples were examined for determination of failure mode using a magnifying lens. Results: The statistically significant highest mean dislodging load value was obtained in IPS e.max Press IRFPDs, followed by IPS e.max CAD, with the least value recorded in breCAM.BioHPP. In contrast, breCAM.BioHPP IRFPDs revealed the statistically significant highest mean fracture load value, followed by BioHPP Granulates, while the least mean fracture value was recorded in IPS e.max Press. Most failure occurred in IPS e.max groups was connector fracture, while in BioHPP groups was plastic deformation. Conclusions: Retention and fracture resistance of metal-free inlayretained bridges are significantly affected by both; material type and construction method. BioHPP has significant advantages for dental applications because of higher fracture resistance and better stress distribution. The bond strength at IPS e.max/ resin cement interface is considered a reliable bond presenting better retention to IRFPDs. Being a brittle material, connector fracture is the predominant failure mode of IPS e.max IRFPDs; however, BioHPP has low elastic modulus showing plastic deformation as a predominant failure mode.