The use of recombinant adeno-associated virus (rAAV) as gene therapy vector for treating liver metabolic diseases is limited by its low transduction efficiency. We describe a strategy for achieving stable and efficient genetic reconstitution in liver after direct administration of rAAV and selective expansion of transduced cells. We have exploited the biology of apoptosis to develop a generic approach for selectively repopulating liver with vector-transduced hepatocytes. Low-level, stable transduction of hepatocytes was achieved by direct injection of rAAV into mouse liver. Expansion of these vector-transduced cells was achieved by incorporating into the construct a minigene expressing Bcl-2 followed by induction of apoptosis in non-vector-containing hepatocytes by systemic administration of a Fas antibody (Ab). Western and Southern blot analysis demonstrated amplification of bcl-2 gene product and viral copy number, respectively, in vector-treated mouse liver when placed under selection. In addition, the percentage of vector transduced cells increased from 2 to 20% after three administrations of Fas Ab, based on immunohistochemical studies.