Background We aimed to investigate the clinical effects of resin nanoceramic (RNC) computer-aided design/computer-aided manufacture (CAD/CAM) partial crowns on posterior teeth after root canal treatment over a 3-year period. Material/Methods A total of 132 posterior teeth restored with CAD/CAM partial crowns were placed in 128 patients. The observation group (n=66) was restored with RNC restorations, while the control group received lithium disilicate-based glass ceramic (LDGC) CAD restorations. Using Fédération dentaire internationale (FDI) World Dental Federation clinical criteria, 2 calibrated evaluators examined the performance of the restorations at baseline, 6, 12, 18, 24, and 36 months. The Kaplan-Meier method and the log-rank test were adopted to analyze the survival rate. The influence of potential risk factors on the main pattern of failure was studied by univariate Cox regression analysis (α=0.05). Results At the 3-year followup, the survival rate of the partial crowns was 83.1% in the RNC group, and 93.5% in the LDGC group ( P =0.061). Failures were caused by debonding (66.7%), restoration fracture (26.6%), and tooth fracture (6.7%). No significant differences were found between the 2 materials at 36 months, except for the parameters of “surface luster” ( P =0.002) and “occlusal contour and wear” ( P =0.009). The RNC group was significantly more likely to debond than the LDGC group (hazard ratio=9.22 [1.17,72.74], P =0.01). Conclusions RNC CAD/CAM-fabricated partial crowns are a potential clinical alternative for endodontically treated posterior teeth, with a survival rate of 83.1% at the 3-year followup. The main pattern of failure was debonding, which might be influenced by surface pretreatment of the RNC material.