Recombinant adeno-associated viral (rAAV) vectors show early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes each having a different transduction profile. Currently, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of the human outcome. In an attempt to better understand these discrepancies, we used a chimeric human-murine liver model to directly compare the relative efficiency of rAAV transduction in human vs. mouse hepatocytes in vivo. As predicted from preclinical and clinical studies rAAV2 vectors transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly – ~20-times less efficiently than mouse hepatocytes. In light of the limitations of rAAV vectors currently used in clinical studies, we used the same murine chimeric liver model to perform serial selection using a human specific replication competent viral library composed of DNA shuffled AAV capsids. One chimeric capsid composed of 5 different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells, and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.