To evaluate surface roughness and bacterial adhesion after in situ biodegradation of the cementation interface of indirect restorations cemented with preheated resin composite. Resin composite blocks (Z250XT/3M ESPE) were cemented to bovine enamel (7 × 2.5 × 2 mm) using preheated microhybrid resin composites: (1) Filtek Z100 (3M ESPE) (Z100); (2) Gradia Direct X (GC America) (GDX); and (3) Light-cured resin cement RelyX Veneer (3M ESPE) (RXV) (n = 21). The resin composites were preheated on a heating device (HotSet, Technolife) at 69°C for 30 minutes. Disk-shaped specimens (7 x 1.5 mm) were made for biodegradation analysis with the luting agents (n = 25). The in situ phase consisted of 20 volunteers' using an intraoral palatal device for 7 days. Each device had six cylindrical wells for the blocks and the disk-shaped specimens. Biodegradation was evaluated through surface roughness (Ra), scanning electron microscopy (SEM) micromorphological analysis, and colony-forming unit (CFU) count. The film thickness of the luting agents was also measured under stereomicroscopy. Increased surface roughness was observed after the cariogenic challenge without differences between the luting agents. Higher variation and surface flaws suggestive of particulate detachment were observed for Z100. No differences were observed in CFU counts. All materials underwent surface biodegradation, and the surface roughness of the resin cements was similar to or lower than that of the preheated resin composites. The resin composites' film thickness was thicker than that of the resin cement. Clinicians should be aware of these factors when choosing the use of preheated resin composite since it can lead to reduced longevity of the cementation interface and, therefore, restorations.