Vectors based on adeno-associated viruses (AAVs) are being evaluated for use in liver-directed gene therapy. Candidates have been preselected on the basis of capsid structure that plays an important role in determining performance profiles. We describe a comprehensive and statistically powered set of mouse studies designed to compare the performance of vectors based on seven novel AAV capsids. The key criteria used to select candidates for successful gene therapy are high level and stable transgene expression in the absence of toxicity. Based on these criteria, the best performing vectors, AAV8, AAVhu.37, and AAVrh.8, will be further evaluated in nonhuman primates (NHPs).