Purpose: Zirconia is being widely used, at times apparently by simply copying a metal design into ceramic. Structurally, ceramics are sensitive to both design and processing (fabrication) details. The aim of this work was to examine four computer-aided design/computer-assisted manufacture (CAD/CAM) abutments using a modified International Standards Organization (ISO) implant fatigue protocol to determine performance as a function of design and processing. Materials and Methods: Two full zirconia and two hybrid (Ti-based) abutments (n = 12 each) were tested wet at 15 Hz at a variety of loads to failure. Failure probability distributions were examined at each load, and when found to be the same, data from all loads were combined for lifetime analysis from accelerated to clinical conditions. Results: Two distinctly different failure modes were found for both full zirconia and Ti-based abutments. One of these for zirconia has been reported clinically in the literature, and one for the Ti-based abutments has been reported anecdotally. The ISO protocol modification in this study forced failures in the abutments; no implant bodies failed. Extrapolated cycles for 10% failure at 70 N were: full zirconia, Atlantis 2 × 107 and Straumann 3 × 107; and Ti-based, Glidewell 1 × 106 and Nobel 1 × 1021. Under accelerated conditions (200 N), performance differed significantly: Straumann clearly outperformed Astra (t test, P = .013), and the Glidewell Ti-base abutment also outperformed Atlantis zirconia at 200 N (Nobel ran-out; t test, P = .035). Conclusion: The modified ISO protocol in this study produced failures that were seen clinically. The manufacture matters; differences in design and fabrication that influence performance cannot be discerned clinically. Keywords: CAD/CAM abutments, fatigue, implant abutments, titanium, zirconia