Two-piece abutments consisting of customized zirconia abutment copings and prefabricated titanium bases are popular due to their biological and esthetic advantages. Glass-ceramic solder (GS) is an alternative biocompatible connective agent. This in vitro study evaluated the retentive force of GS in comparison to classical resin composite cements (RC) after artificial aging and autoclaving. Ninety specimens consisting of prefabricated titanium bases and zirconia abutment copings were fabricated. The two parts of each specimen were fixed either by RC (n = 30) or GS with a luting space of either 30 µm (n = 30) or 100 µm (n = 30). Ten specimens of each group underwent autoclaving before artificial aging (water storage, thermocycling). Twenty specimens (including the 10 autoclaved specimens) of each group were exposed to a mechanical load. The retentive force between the zirconia and titanium in all specimens was determined. A fractographic analysis was performed to analyze the fracture surfaces of the GS specimens. The RC- and GS-connected two-piece abutments showed no relevant differences, independent of the luting space. RC appears to be more vulnerable to the thermal and mechanical loads than GS. Thus, GS may be an appropriate alternative to RC for two-piece abutments, especially for patients with enhanced biocompatibility requirements.