The predominant source of alveolar macrophages is monocytic migration with a smaller proportion arising from dividing interstitial cells. To determine how this system responds to particulate loading when depleted of monocytes, mice received 650 rad whole body irradiation followed by 4 mg carbon instilled into the trachea. Control groups included irradiated mice given no carbon and nonirradiated mice given carbon. After irradiation alone, the number of monocytes fell to a very low level for at least 3 wk, whereas the output of alveolar macrophages remained normal. In nonirradiated mice, carbon induced a tenfold increase in macrophages the first day, dropping rapidly after 1 wk. Macrophage output in irradiated animals given carbon doubled the first day, then rose to 4 times normal after 2 wk. This limited response to carbon was accompanied by increased DNA synthesis in pulmonary interstitial cells, but the number of circulating monocytes and labeling of alveolar macrophages remained very low. The results indicate that when monocytes are not available, output of alveolar macrophages is maintained by precursor cells in the pulmonary interstitium. This interstitial compartment provides an essential back-up mechanism capable of responding to increased particulate loading in both normal and monocytopenic animals.