125I-Mannose-BSA is taken up by alveolar macrophages by receptor-mediated endocytosis. Uptake is macrophage-specific and does not occur in polymorphonuclear leukocytes. Binding (4°C) and uptake (37°C) of 125I-Man-BSA are time- and ligand concentration-dependent [Kuptake = 40 nM; Kd (4°C) = 10 nM]. When adjusted for ligand degradation, ligand uptake is linear with time. Binding saturates at 60 min and requires Ca++. Following binding, ligand remains on the cell surface where it can be released by EGTA and trypsin. Internalization of prebound ligand occurs very rapidly (t 1 2 <5min) when cells are warmed to 37°C. Following internalization of prebound ligand, binding activity is rapidly recovered (t 1 2 <5min). Trypsin treatment (4°C) substantially reduces binding activity (>70% per 30 min). However, binding activity is rapidly recovered in cells treated with trypsin at 4°C by warming to 37°C in the absence of added ligand. Trypsin treatment at 37°C rapidly destroys binding and uptake. On the contrary, 4°C trypsin treatment produces only a modest reduction in subsequent ligand uptake. These results, taken together with the observation that cycloheximide has no effect on ligand uptake, suggest that receptors must be spared from degradation and that reutilization of receptors probably occurs.