DNA-anti-DNA immune complexes play a major role in the pathogenesis of SLE. Evidence suggests that the DNA contained within these complexes, as well as free circulating DNA, is of small molecular weight and predominantly double stranded. Previous studies have shown that large DNA is cleared from circulation rapidly and efficiently. To examine if variations in the configuration of DNA itself affected its ability to persist in the circulation, we studied the clearance and organ uptake of single stranded DNA(ssDNA) and double stranded DNA(dsDNA) of different sizes in normal mice. Clearance of DNA from the circulation was described by two exponential components. The first component represented organ uptake, and was much more rapid for ssDNA than for dsDNA. The second component represented the excretion of breakdown products from the total body pool, and was the same for all DNA preparations. Regardless of its initial size, DNA larger than 15 bases did not persist in the circulation longer than 20 min for ssDNA, and longer than 40 min for dsDNA. Organ distribution studies showed that ssDNA was removed by the liver, but that dsDNA bound poorly to the liver and was distributed like oligonucleotide breakdown products. Our results suggest that dsDNA and ssDNA are removed from the circulation by different mechanisms. Although dsDNA remains in the circulation slightly longer than ssDNA, all DNA, regardless of its size or strandedness, is cleared from the circulation and broken down rapidly and efficiently.