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We have previously shown that hyperbranched multi-methacrylate (H-MMA)-modified dental resins have VLC activities, lower polymerization shrinkage, and improved mechanical properties, compared to the 2,2-bis[4-(2-hydroxy-3-methacryloyolxypropoxy)phenyl]propane/triethyleneglycol dimethacrylate (BisGMA/TEGDMA) neat resin. The results are due to the unique molecular structure and high molecular weight of H-MMA intermediates. The purpose of this study was to evaluate the biocompatibility of H-MMA-modified dental neat resins. The cell proliferation of three human gingival fibroblast strains on either H-MMA, BisGMA/TEGDMA, or a polystyrene disk was examined. Following 10 days of cell proliferation, there was no statistical difference in cell number between H-MMA-modified and unmodified resin disks. H-MMA-modified resins had less free monomer leaching than the unmodified resin but showed similar properties in water sorption and contact angle values. All these results suggest that the biocompatibility of H-MMA-modified dental neat resins is as good as that of commercially used BisGMA/TEGDMA resin and H-MMA has potential applications in dental composites.