Exposure to nanoparticles has presented potential risks to human cardiorespiratory systems. Pulmonary retention and extrapulmonary redistribution of inhaled nanoparticles have been considered to be important contributing factors of cardiorespiratory diseases. In the present work, 22-nm (59)Fe(2)O(3) nanoparticles (radioactive isotope (59)Fe-labeled ferric oxide nanoparticles) were intratracheally instilled into the male Sprague-Dawley rats at a dose of 4 mg/rat. Extrapulmonary distribution of (59)Fe(2)O(3) in organs and its metabolism in lung, blood, urine, and feces were measured for 50 days of exposure. Phagocytosis and clearance of agglomerated nano-Fe(2)O(3) by monocytes/macrophages were observed by histopathology and inductively coupled plasma-mass spectrometry examination. Our results showed intratracheal-instilled nano-(59)Fe(2)O(3) could pass through the alveolar-capillary barrier into systemic circulation within 10 min that consisted with one-compartment kinetic model. The nano-(59)Fe(2)O(3) in the lung was distributed to organs rich in mononuclear phagocytes, including liver, spleen, kidney and testicle. The plasma elimination half-life of nano-(59)Fe(2)O(3) was 22.8 days and the lung clearance rate was 3.06 microg/day, indicating the systemic accumulation and lung retention had occurred. The deposited nano-Fe(2)O(3) in interstitial lung was probably contributed by the particles escaping from alveolar macrophages phagocytosis and macrophages clearance function overloading. Our results suggest that the effect of Fe(2)O(3) nanoparticles exposure, even at low concentration, should be assessed because of the potential lung and systemic cumulative toxicity of the nanoparticles.