Naked DNA is regarded as the safest and simplest method of gene delivery. However, normally intravenously injected naked plasmid DNA is rapidly eliminated from the blood. It has been hypothesized that opsonins, a category of serum DNA-binding proteins (SDBPs), label the injected plasmid DNA as foreign so that it may be recognized and rapidly removed from the bloodstream by liver nonparenchymal cells. Contrary to the hypothesis, our data indicate that some SDBPs across multiple species may have important dysopsonin properties, acting to reduce liver uptake. Formation of SDBP and DNA complexes was observed by agarose gel electrophoresis. An in vivo study involving hepatic artery and portal vein occlusion in a mouse model confirmed the activity of serum diminishing liver uptake of DNA. Data using hydrodynamic gene transfer in the mouse liver and in situ transfection in the mouse lung revealed that serum proteins bound to DNA do not affect the biological activity of the plasmid DNA. We have identified several SDBPs with potential dysopsonin properties. The SDBPs with dysopsonin properties and DNA complexes may be further modified and ultimately be developed into a novel DNA carrier system favorable for systemic gene delivery.