The present study evaluated the participation of the primate erythrocyte immune complex (IC) clearing mechanism in the clearance and organ uptake of double-stranded DNA (dsDNA) and of soluble ICs formed with human anti-DNA antibodies and dsDNA (dsDNA-ICs). Five baboons received 51Cr-labeled autologous erythrocytes and after a period of equilibration received separate intraarterial injections of [125I]free dsDNA and [125I]dsDNA-IC. Four of these five baboons were studied on a second occasion. To assess clearance from the arterial circulation and organ uptake, multiple blood samples were obtained from aorta, hepatic vein, and renal vein after injection of each probe. Two minutes after injection, a mean of 85% of dsDNA-ICs were bound to erythrocytes. By contrast, free dsDNA did not bind significantly to blood cells. The clearance rate of dsDNA-ICs from the arterial circulation was significantly faster than that of free dsDNA in all animals but one. Erythrocyte-bound dsDNA-ICs were cleared at a rate similar to that of total dsDNA-ICs. The liver was the major site of uptake of free dsDNA and of dsDNA-ICs. The hepatic uptakes of free dsDNA (17 +/- 8%/5 min) and dsDNA-ICs (27 +/- 8%/5 min) were not significantly different. 51Cr-labeled erythrocytes were not sequestered in the liver. There was not detectable uptake of free dsDNA or dsDNA-ICs by the kidney but with one exception. Thus, the primate erythrocyte IC clearing mechanism is involved in the clearance of dsDNA-ICs from the circulation but not in the clearance of free dsDNA.