Alveolar macrophages (AM) and peritoneal macrophages (PM) originate from common precursor cells, but function in different O2 environments. In the present studies, the impact of different O2 tensions on cell metabolism has been quantitatively determined, an enzymatic basis for these differences established, and a mechanism which regulates enzymatic differences demonstrated. O2 consumption and lactate production were compared in rabbit AM and PM in air and nitrogen. In air, AM demonstrate significantly greater O2 utilization. In nitrogen, (where glycolysis is the major source of energy provision) lactate production is two- to threefold greater in the PM. A comparison of several enzymes of energy metabolism in AM and PM indicate that one basis for the differences in cell energetics is a difference in activity of key enzymes of both the oxidative phosphorlyative and the glycolytic sequences. Exposure of cultivated AM to hypoxic conditions results in changes in the activity of these enzymes such that the AM closely resembles the PM. A key enzyme in oxidative phosphorylation (cytochrome oxidase) shows decreased activity and reaches values similar to those found in the PM. A key enzyme in glycolysis (pyruvate kinase) shows increased activity to values resembling those found in the PM. These alterations in enzyme pattern occur in isolated cell systems, suggesting that molecular O2 modifies the intrinsic cellular regulation of some enzymes of energy metabolism. Alterations in O2 tension may lead to alterations of the rate of biosynthesis and (or) the rate of biodegradation of key enzymes involved in oxidative phosphorylation and glycolysis. In turn, the alteration of enzyme patterns leads to a more suitable bioenergetic pattern as a function of O2 availability.