In this study, the cytotoxicity of different combinations of contemporary resin-based restoratives (adhesives, composites, luting agents) against human keratinocytes (HaCaT) was evaluated under two conditions, whether materials were applied to dentin or not. Adhesives (3-step etch-and-rinse/3ER: OptiBond FL; 2-step self-etch/2SE Clearfil SE Bond; Single Bond Universal/UNI), composites (conventional composite resin/CCR: Filtek Z350XT; flowable/FCR: Filtek Z350XT Flow; self-adhesive composite resin/SACR: Dyad Flow), and luting agents (conventional luting agent/CLA: Variolink-II; self-adhesive luting agent/SLA: RelyXU200) were combined according to their clinical use. Eluates from polymerized specimens applied to dentin were placed in contact with cells grown for 1 and 7 d. The controls were defined by cells without material contact. Cell viability was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. C=C conversion was investigated using Fourier-transform infrared spectroscopy. After 1 d of incubation, when dentin was not present, 2SE yielded the highest cell viability, whereas 3ER, UNI, and SACR showed higher cell viability in the presence of dentin. After 7 d, when dentin was absent, 2SE and CLA achieved significantly higher cell viability. The presence of dentin resulted in a drastically higher cell viability for all materials, except 2SE and CLA. UNI had the lowest C=C conversion. The presence of dentin was a significant factor, which resulted in higher cell viability than what was seen for the material specimens per se. All materials resulted in a lower viability of HaCaT than what was seen under the no-material control conditions, with effects mainly limited to the first 24 h.