The use of the cone-in-cone connection to support definitive restorations was previously evaluated in cases involving full-acrylic resin or hybrid acrylic-resin composite prostheses. The aim of this study was to evaluate the performance of definitive fixed partial prostheses made with monolithic zirconia and supported by cone-in-cone abutments and integrated implants. Implants were placed into healed sites and fresh extraction sockets. The prostheses were placed in the posterior regions of partially edentulous patients after healing periods of 3 months. A total of 76 patients received fixed monolithic zirconia restorations splinted with cone-in-cone connections to two implants that were followed up yearly for 5 years. At each follow-up visit, peri-implant bone levels and pocket depths were recorded. Esthetic, functional, and biologic United States Public Health Services parameters modified by the World Dental Federation study design were assessed at the last follow-up appointments. The opposing dentition was categorized by type of restoration and supporting structure at the time of placement of the definitive zirconia partial restoration and at the 5-year follow-up. The treatment achieved an 88.2% success rate and a 97.4% survival rate at the 5-year follow-up. None of the prostheses became loose or detached. One fixed prosthesis (0.76%) fractured 41 months after placement. No significant difference involving peri-implant bone and probing levels between the experimental times was found. The results of this research indicated that abutment-prosthesis cone-in-cone connections were successful within the 5-year study period.