In this study, we identified the toxic effects of sheet-type titania (TNS), which are being developed as a material for UV-blocking glass, comparing with P25, a benchmark control for titania, in MH-S cells, a mouse alveolar macrophage cell line. After 24 h exposure, the TNS-exposed cells formed large vacuoles while the P25-exposed ones did not. The decreased levels of cell viability were similar between the P25 and TNS groups, but ATP production was clearly lower in cells exposed to the TNS. P25 decreased the expression of calnexin protein, an endoplasmic reticulum (ER) membrane marker, and increased the number of cells generating ROS in a dose dependent manner. Meanwhile, TNS dilated the ER and mitochondria and increased the secretion of NO and pro-inflammatory cytokines, but not of ROS. Subsequently, we studied the molecular response following TNS-induced vacuolization. TNS started to form vacuoles in the cytosol since 20 min after exposure, and the expression of the mitochondria function-related genes were down-regulated the most in the cells exposed for 1 h. After 24 h exposure, the number of apoptotic cells and the relative levels of BAX to Bcl-2 increased. The expression of SOD1 protein, but not of SOD2, also dose-dependently increased with an increase in caspase-8 activity. Additionally, the MAPK pathway was significantly activated, even though the expression of p-EGFR did not change significantly. Furthermore, the number of apoptotic cells increased rapidly with time and with the inhibition of vacuole formation. Taken together, we suggest that P25 and TNS may target different organelles. In addition, TNS, but not P25, induced paraptosis accompanied by apoptosis in MH-S cells, and the formation of the cytoplasmic vacuoles allowed delay apoptosis following TNS exposure.