Particulate matter with an aerodynamic diameter of less than 2.5 μM (PM2.5) is one of the major environmental pollutants. Di(2-ethylhexyl) phthalate (DEHP), an endocrine disrupting chemical in PM2.5, has been utilized for the manufacturing of polyvinyl chloride to increase the flexibility of final products. In the present study, we investigated the ecotoxicological effect of DEHP on the viability of skin keratinocytes (HaCaT). DEHP induced apoptotic cell death mediated by phosphorylation of extracellular signal-regulated kinase through the production of intracellular Reactive Oxygen Species (ROS). Interestingly, we found that DEHP induces the phosphorylation of the nuclear factor-kappa B responsible for the expression of cleaved caspase-3 as an executional cell death protease in HaCaT cells. On the basis of these results, we suggest that DEHP in PM2.5 induces the apoptotic death of human keratinocytes via ROS-mediated signaling events.