Background: Recent introduction of computer-aided design/computer-aided manufacturing (CAD/CAM) monolithic zirconia dental prostheses raises the issue of material low thermal degradation (LTD), a wellknown problem with zirconia hip prostheses. This phenomenon could be accentuated by masticatory mechanical stress. Until now zirconia LTD process has only been studied in vitro. This work introduces an original protocol to evaluate LTD process of monolithic zirconia prostheses in the oral environment and to study their general clinical behavior, notably in terms of wear. Methods/design: 101 posterior monolithic zirconia tooth elements (molars and premolars) are included in a 5-year prospective clinical trial. On each element, several areas between 1 and 2 mm(2) (6 on molars, 4 on premolars) are determined on restoration surface: areas submitted or non-submitted to mastication mechanical stress, glazed or non-glazed. Before prosthesis placement, ex vivo analyses regarding LTD and wear are performed using Raman spectroscopy, SEM imagery and 3D laser profilometry. After placement, restorations are clinically evaluated following criteria of the World Dental Federation (FDI), complemented by the analysis of fracture clinical risk factors. Two independent examiners perform the evaluations. Clinical evaluation and ex vivo analyses are carried out after 6 months and then each year for up to 5 years. Discussion: For clinicians and patients, the results of this trial will justify the use of monolithic zirconia restorations in dental practice. For researchers, the originality of a clinical study including ex vivo analyses of material aging will provide important data regarding zirconia properties. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license