Dental composite materials can exert different effects. Particularly, monomers could influence the odontogenic differentiation in human dental pulp stem cells (hDPSCs). This preliminary study aimed to evaluate cytotoxicity of two novel composites and whether they can affect mineralization of hDPSCs. Ceram.x Spectra^TM, a nanohybrid composite with pre-polymerized Sphere-Tec particles, and Admira Fusion, a nanohybrid restorative material with the innovative technology ORMOCER were tested. The samples and the eluates were prepared according to ISO 10993-12:2012. We treated hDPSCs in undifferentiated state with eluates for 4 days and performed MTT assay to evaluate cytotoxicity. The effect of the eluates on the hDPSCs mineralization capacity was evaluated after osteogenic differentiation by alizarin red staining and alkaline phosphatase (ALP) activity test. We assessed different dilutions of both eluates and observed that undiluted Ceram.x eluates were significantly cytotoxic over time, reducing cell viability of about 51,7% as compared to untreated cells. Further, the eluates obtained from ORMOCER technology composite did not display any adverse effect on hDPSCs viability. Moreover, we assessed that Ceram.x limited osteogenic activity of hDPSCs, while Admira Fusion did not appear to show any adverse effect. Our results show that composite with conventional dental monomer might exert cytotoxicity on hDPSCs as compared to ORMOCER technology. Indeed, the limited cell differentiation caused by Ceram.x could be explained by its cytotoxic effect. In this regard, the study is continuing to define cellular changes induced by the composites and to further identify the optimal dental composite resin for clinical use.