Inhaled particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM2.5) has been demonstrated to induce season-dependent adverse health effects. Given the critical role that inflammation and oxidative stress play in PM2.5-induced health effects, this study investigated whether PM2.5-induced oxidative stress and pro-inflammatory response varied with season using a human monocytic cell line, THP-1. PM2.5 was collected in April (spring), July (summer), September (fall) and December (winter) of 2014. Cytotoxicity was assessed by lactate dehydrogenase (LDH) release assay. The levels of pro-inflammatory mediators including tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) were measured with ELISA. Reactive oxygen species (ROS) were determined with flow cytometry. Sulforaphane (SFN), an antioxidant, was used to determine whether ROS regulated PM2.5-induced expression of pro-inflammatory mediators. It was shown that winter PM2.5 was more potent in inducing cytotoxicity than the PM2.5 from other seasons. Similarly, winter PM2.5 induced more production of TNF-α and IL-1β from THP-1 cells than other PM2.5 at the same dose. The same was true of ROS production. Further studies demonstrated that pretreatment of THP-1 cells with SFN markedly blunted the winter PM2.5-induced release of TNF-α and IL-1β. Composition analysis revealed that summer and winter PM2.5 contained higher levels of anion (NO3- and SO42-) and water-soluble metals (Al, Ca, Mg, Zn and Cr) than the PM2.5 from other seasons. In summary, PM2.5-induced oxidative stress and subsequent production of pro-inflammatory mediators varies with season.