Recent evidences show inhaled PM2.5 can enter the blood circulation and even the brain. However, the damages of blood-borne PM2.5 are not clearly elucidated. This work aimed to understand and characterize how toxic, i.e., its acute health effects, when PM2.5 is directly injected into the blood circulation. Rats were injected with different doses (568-equivalent of 1-year rat inhalation dose, 93 and 9.3 µg) of PM2.5 sampled from Beijing via a sterile catheter cultivated into the jugular vein. The behaviors of rats upon external interruptions were recorded. Blood samples were collected before exposure and 1h, 3 days, 5 days, 7 days, 9 days after the PM2.5 injection for analyzing serum interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), endotoxin and 8-hydroxydeoxyguanosine (8-OHdG) levels. After euthanization, heart, lung, liver, kidney and spleen were taken and processed for histopathological analysis. PM2.5 components were also analyzed. Acute inflammation with 102% and 90% increases for IL-6 and CRP, respectively, was observed 1 h after the 568 µg PM2.5 injection; while oxidative DNA damage occurred only five or more days later, which was accompanied with significantly elevated endotoxin level. Hemorrhage in lung alveoli and behavioral changes including fear and non-responsiveness were also observed. Surprisingly, all exposed rats seemingly survived the PM2.5 injection, i.e., behaving similarly with the control groups. The immune defense might have played an important role in combating the PM2.5 injection. The results showed acute health effects of directly injected PM2.5, including rapid inflammation, oxidative damages and routine behavioral changes. The long-term effects of the injection and in-depth study about the immune defense are further warranted. Nonetheless, the results here suggest that PM2.5 health effects could have been exaggerated in the literature.