This study evaluated the fracture resistance of teeth with mesio-occluso-distal (MOD) resin composite restorations using universal adhesive (Single Bond Universal; SBU) in three different manipulation modes compared with those using two-step self-etch (Clearfil SE bond; CSE) and 3-step etch-and-rinse (Scotchbond Multi-Purpose; SBMP) adhesives at 24 hours and after thermocycling. One hundred and sixty maxillary premolars were assigned into eight groups of 20 each. Intact teeth and nonrestored cavity-prepared teeth served as controls. For the remaining specimens, cavities were restored with resin composite using different adhesives—SBU in self-etch, etch-and-rinse, or selective enamel etching modes; CSE in self-etch or selective enamel etching; and SBMP. Specimens from each group were either stored in 37°C water for 24 hours or further submitted to thermocycling for 30,000 cycles (n=10), then subjected to axial compression stress until fracture. Fracture patterns were observed microscopically. Data were statistically analyzed at a 95% confidence level. Among the restored teeth, mean failure load of the group using SBMP was the highest at both short-term and long-term evaluation periods (p<0.05). Fracture strengths of the SBU groups where enamel was etched with phosphoric acid prior to the adhesive application were similar and were greater than in those specimens without pre-etching (p<0.05). After thermal aging, a significant decrease in fracture resistance value was detected only for the group using SBU in etch-and-rinse application mode (p<0.05). For the self-etch strategy, SBU demonstrated lower load to fracture than CSE following thermocycling; all specimens failed at and beneath the crestal level (p<0.05). Application of SBU universal adhesive in selective enamel etching mode provided higher and more stable fracture resistance of teeth with MOD resin composite restorations than in self-etch mode.