The hydrodynamic injection in mice tail vein of a plasmid (40 µg DNA) bearing the human α1-antitrypsin gene mediates: a) good liver gene transfer resulting in therapeutic plasma levels of human protein (>0.9 mg/ml); b) low liver injury as evaluated by a small and transient increase in AST and ALT in mouse plasma; and c) limited expression changes in host liver genes as evaluated by microarray analysis on days 2 and 10 after injection. For microarray analysis, groups of three mice were uninjected (control) or hydrodynamically injected with saline or plasmid DNA and then sacrificed on days 2 and 10 after injection. The results indicate that approximately 20 genes were up-regulated, whereas more than 50 genes were down-regulated. The most important change in up-regulated gene expression corresponded to the serum amyloid A group and the orosomucoid gene. Also, increased expression was observed of genes involved in contractile functions (actin, myosin, troponin) and lipid metabolism (lipin 1 and apolipoprotein A-IV). Relatively more genes were down-regulated, though only a few such as CYP4A10, ATP-binding cassette ABC1, peroxisomal acyl-CoA thioesterase 2A, phospholipids and phosphatidylcholine transfer protein, appear to be mediated by the presence of DNA in the solution. Although hydrodynamic injection appears to mediate only limited changes in host gene expression in the liver, some of the down-regulated genes are associated to atherosclerosis or hypertension diseases. Thus, additional studies will be necessary to clarify the long-term effect of the hydrodynamic gene transfer procedure.