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 ⁵⁹Fe₂O₃ nanoparticles (radioactive isotope ⁵⁹Fe-labeled ferric oxide nanoparticles) were intratracheally instilled into the male Sprague-Dawley rats at a dose of 4 mg/rat. Extrapulmonary distribution of ⁵⁹Fe₂O₃ in organs and its metabolism in lung, blood, urine, and feces were measured for 50 days of exposure. Phagocytosis and clearance of agglomerated nano-Fe₂O₃ by monocytes/macrophages were observed by histopathology and inductively coupled plasma-mass spectrometry examination. Our results showed intratracheal-instilled nano-⁵⁹Fe₂O₃ could pass through the alveolar-capillary barrier into systemic circulation within 10 min that consisted with one-compartment kinetic model. The nano-⁵⁹Fe₂O₃ in the lung was distributed to organs rich in mononuclear phagocytes, including liver, spleen, kidney and testicle. The plasma elimination half-life of nano-⁵⁹Fe₂O₃ was 22.8 days and the lung clearance rate was 3.06 μg/day, indicating the systemic accumulation and lung retention had occurred. The deposited nano-Fe₂O₃ 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 Fe₂O₃ nanoparticles exposure, even at low concentration, should be assessed because of the potential lung and systemic cumulative toxicity of the nanoparticles.