The effect of cyclophosphamide on the absolute numbers and function of alveolar macrophages following either in vitro or in vivo drug exposure was studied in the guinea-pig. Two separate regimens of in vivo cyclophosphamide administration (100 mg/kg/one dose or 20 mg/kg for 5 days) both of which produce identical decreases in each population of peripheral blood leucocytes 5 days after the initial injection did not produce anay change in alveolar macrophage numbers when compared to control values. Neither a brief exposure to CY in vitro nor a brief exposure in vivo (100 mg/kg/one dose) caused any change in cytotoxic effector function of alveolar macrophages using the PHA-induced and antibody-dependent cellular cytotoxicity assays against sheep erythrocyte targets. In contrast, the more prolonged in vivo exposure to CY (20 mg/kg for 5 days), produced a significant decrease in the killer cell function of these cells. Thus, this study demonstrates that different regimens of cyclophosphamide administration, although producing similar degrees of peripheral blood leucopenia can produce markedly different effects on the functional capabilities of alveolar macrophages without quantitatively decreasing the absolute numbers of these cells.