The phototoxicity of ultraviolet A irradiation (UVA) can be enhanced by photosensitizing agents, such as titanium dioxide nanoparticles (100 nm in diameter, "normal-TiO₂"). Nano-TiO₂ treatment in the absence of UVA caused a slight decrease in cell viability, but in the presence of UVA, it caused a significant decrease in cell viability. In the presence of UVA, nano-TiO₂ also significantly increased the percentage of the cell population in the sub-G₁ phase, induced activation of the proapoptotic proteins, caspase-9, caspase-3, and poly(ADP)ribose polymerase, significantly increased the production of reactive oxygen species (ROS), and induced the loss of the mitochondrial membrane potential (MMP), suggesting that UVA and nano-TiO₂ synergistically promoted apoptosis via a mitochondrial pathway. In the presence of UVA, but not in its absence, nano-TiO₂ treatment also caused a significant increase in DNA damage. Normal-TiO₂ used at the same concentrations did not cause DNA damage, induce ROS generation, trigger mitochondrial membrane depolarization, or increase apoptotic cell death, regardless of UVA exposure. Taken together, these results suggest that nano-TiO₂ and UVA synergistically promote rapid ROS generation and MMP collapse, triggering apoptosis. Additionally, they show that small TiO₂ particles are more phototoxic than larger ones.