Aim: This study compared the fracture resistance of endodontically-treated mandibular molars with mesio-occluso-distal (MOD) cavities restored using different restoration techniques. Methodology: Sixty sound extracted mandibular molars were randomly assigned to six groups (n=10). Group 1 did not receive any preparation. The teeth in Groups 2-6 received root canal treatment and a MOD cavity preparation. The teeth in Group 2 were kept unrestored. Group 3 was restored conventionally with amalgam. Group 4 was restored with a dentin bonding system (DBS, Clearfil SE Bond) and resin composite (CR) (Clearfil Photoposterior). Group 5 was restored with indirect hybrid ceramic inlay material (Estenia). In Group 6, polyethylene ribbon fiber (Ribbond) was inserted into cavities in a buccal-to-lingual direction and the teeth were then restored with DBS and CR. After finishing and polishing, the specimens, except for Group 2, were loaded to failure by a chewing simulation device (60,000 cycles × 50 N load, 1.3 Hz frequency) in an artificial environment at 37°C. Each tooth was subjected to compressive loading perpendicular to the occlusal surface at a crosshead speed of 1 mm/minute. The mean loads necessary to fracture were recorded in Newtons and the results were statistically analyzed. Results: The mean fracture values were as follows: Group 1: 2485.3 ± 193.9 a, Group 2: 533.9 ± 59.4b, Group 3: 1705.8 ± 135.7c, Group 4: 2033.3 ± 137.6cd, Group 5: 2121.3 ± 156.5d, Group 6: 1908.9 ± 132.2cd. There were statistically significant differences between the groups annotated with different letters. Thus, Group 1 (intact teeth) had the greatest fracture resistance and Group 2 (non-restored teeth) the poorest. No statistically significant differences were found between Groups 3 (amalgam), 4 (resin composite) and 6 (polyethylene ribbon fiber reinforced composite) (p>0.05). Group 5 (indirect hybrid ceramic inlay) had greater fracture resistance than Group 3 (p<0.05). Conclusions: Within the limitations of this study, although all of the restoration groups were stronger than the prepared-only group, none of the restoration techniques tested was able to completely restore the fracture resistance lost from MOD cavity preparation. However, use of indirect hybrid inlay restorations in these teeth may be recommended, because this restoration technique indicated more favorable fracture failure modes than other restoration techniques used in this study and particularly greater fracture strength than amalgam restorations. The promising result of indirect hybrid inlay restorations may need to be confirmed by long-term clinical studies. © Operative Dentistry, 2008.