The aim of this study was to compare the effect of three different access cavity designs on fracture resistance of endodontically treated upper first premolars restored with two different coronal cavity designs. Materials and Methods: Seventy two upper first premolars were selected and divided into three equal groups: Group I, traditional endodontic access cavity (TEC); Group II, conservative endodontic access cavity (CEC); Group III, Truss endodontic access cavity (TUS). Each group was further subdivided into two equal subgroups according to the coronal cavity design either with or without cusp tipping preparations (CTP) or (CCP) respectively (n = 12/subgroup). According to the assigned subgroup, teeth were endodontically treated and restored with nanohybrid resin composite with etch and rinse adhesive system. Samples were mounted in a universal testing machine, loaded to failure and fracture strength was measured in Newton (N). Data were statistically analyzed by two-way ANOVA and Tukey's post hoc significance difference test were used to analyze the data. Results: Two-way ANOVA showed that different designs of endodontic access cavities and different types of coronal cavity preparations used in the study had a significant effect on fracture resistance. Conclusions: TUS access cavity preparation had a positive influence on fracture resistance of root canal treated maxillary premolars. Direct cusp coverage improved the fracture resistance of root canal treated maxillary premolars compared to direct intra coronal restorations. Combining the use of cusp coverage coronal cavity design in restoring root canal treated maxillary premolars with TEC or CEC access cavities may be beneficial.