A growing body of research supports the development of recombinant adeno-associated viral vectors (rAAV) for delivery of gene expression cassettes to striated musculature as a method of treating severe neuromuscular conditions. However, it is unclear whether delivery protocols that achieve extensive gene transfer in mice can be adapted to produce similarly extensive gene transfer in larger mammals and ultimately patients. In order to further understand vascular rAAV gene delivery properties, and potentials for enhancement, we examined rAAV6 reporter gene transduction in adult mouse and canine musculature. A dose escalation study of IV-injected rAAV6 into mice clarified that once an apparent dose threshold is surpassed, transgene expression levels in muscles increase logarithmically over a linear range of doses. Furthermore, including empty capsids (carrying no vector genome) at a subthreshold vector genome dose enhances transgene expression levels greater than 10-fold, on a muscle- and capsid serotype-specific basis. An equivalent addition of genome-carrying rAAV6 capsids increases transgene expression above that produced by empty capsids only 2-4 fold. We therefore conclude that much of the logarithmic expression increase beyond the dose threshold is due to capsid concentration. Comparisons between transgene expression levels and vector genome presence in muscle tissue indicate that empty capsids effect expression increases largely by intracellular mechanisms in target cells. We also tested techniques for delivering rAAV6 to canine striated muscle via intravascular infusion. We found that a simple procedure incorporating acute (a) occlusion of limb blood flow, (b) exsanguination via compression bandage, and (c) vector "dwell" time of < 20 minutes, markedly enhances the transduction of limb muscles, compared with a simple bolus limb infusion of vector. A complementary method whereby vector is infused into the jugular vein leads to efficient transduction of cardiomyocytes and to a lesser degree the diaphragm. These results establish that for efficient rAAV transduction of striated muscle, a capsid concentration-dependent dose threshold must be overcome, and that rAAV-mediated gene delivery is a viable approach to achieving systemic transduction of striated musculature in mammals approaching the dimensions of newborn humans.