Background: Classic endocrowns made of dental ceramics are considered a promising alternative to traditional post-endodontic restorations. The use of circular ferrules in endocrowns is a topic of controversial discussion. Therefore, the present study aims to evaluate the effect of ferrule design and cementation mode on the fatigue resistance of zirconia endocrowns. Methods: Eighty human molars were divided into four groups (n = 20): NFC (no-ferrule, conventional cementation), NFA (no-ferrule, adhesive luting), FC (ferrule, conventional cementation) and FA (ferrule, adhesive luting). Both the classic and the modified endocrown preparation with a two-millimeter ferrule design were carried out. Endocrowns were fabricated from zirconia using the CEREC system. After thermocycling, specimens were loaded according to the step-stress test up to 1500 N. Results: Failure rate was low; 88.8% of total specimens passed the step-stress test. Fractures were distributed between all groups; no significant differences in fatigue resistance were detected for preparation design and cementation mode. Conclusions: Endocrowns appear to be a promising concept for endodontically treated molars. Ferrule and also cementation mode have only a minor influence on fatigue resistance of zirconia endocrowns. However, at very high forces, the marginal area of the ferrule represents a weak point.