This study compared the fracture resistance of monolithic and veneered all-ceramic four-unit posterior fixed dental prostheses (FDPs) generated by computer-aided design/computer-aided manufacturing (CAD/CAM) after aging in a mastication simulator. Four-unit FDPs were designed from six different all-ceramic systems: 1) monolithic lithium disilicate (M-E), 2) monolithic zirconia (M-TZI), 3) veneered zirconia by conventional layering (V-L), 4) veneered zirconia by lithium disilicate pressing (V-P), 5) veneered zirconia by lithium disilicate fusing (CAD-F-E), and 6) veneered zirconia by feldspathic ceramic cementing (CAD-C-CB). The specimens were divided into control and aging groups (n = 10 per group). The aging process included both thermocycling and mechanical loading and was followed by fracture resistance testing. All specimens in the ME , M-TZI, and V-L groups survived; however, all specimens in the V-P group were fractured during artificial aging. The highest fracture resistance values were observed in the M-TZI group. According to the fracture resistance test, connector fractures were the most frequent type of failure. M-TZI and ME FDPs revealed no failures during aging and showed higher fracture resistance than the veneered groups. Among the veneered zirconia framework groups, V-L FDPs showed the highest success rate during aging, while the fracture resistance was similar among all the veneered zirconia groups.