Objectives: Some reports suggest that certain bio-active restoratives stimulate remineralization and also provide long-term toughness. The purpose of this study was to investigate changes to the nanohardness of artificial carious lesions following the in vitro restoration with GIOMER bio-active restorative materials at 1, 4 & 12-weeks. Materials & Methods: Class I cavities were placed throughout teeth of extracted human third molars with each cavity then subjected to lactic acid and cariogenic bacteria (S. mutans). The in vitro caries was removed with a low speed round bur and the cavity restored with one of three-materials. Two GIOMER restorative systems (Shofu) including S-PRG (surface reaction type Pre-Reacted Glass-ionomer) filler; FL-BONDII & BEAUTIFILII(FL-II), Fluoro Bond Shake One & BEAUTIFIL Flow (SO). Clearfil SE Bond & Clearfil Majesty LV (Kuraray Medical) served as SE-control. Each material was placed per manufacture's directions. After restoration, Ringer's solution at a hydrostatic fluid pressure of 15cm of H2O was maintained to the pulp chamber of each tooth and stored at 37°C in 100% relative humidity for either 1-week (1w), 4-weeks (4w) or 12-weeks (12w). After storage, each specimen was cut perpendicular to the resin-dentin interface & each half surface polished. The nanohardness site of each resin-dentin interface was measured using a 1mN load-each site at a 5µm pitch from cavity floor to 100µm & 100µm pitch from 100µm to 500µm. Each site was measured at 10-points in a horizontal direction with 3-measurements for each specimen. Nanohardness compared one-way ANOVA, Tukey's test (a=0.05). Results: Nanohardness of the dentin interface compared FL-II & SO to SE-control at 12w, FLII & SO demonstrated increased nanohardness values against the SE-control. Conclusion: Our data suggest that in vitro dentin remineralization occurs to the cavity dentin subjacent to the GIOMER bio-active restoratives with S-PRG filler after 12w.