Control of transgene expression from long-term expression vectors can be achieved with inducible and regulated promoters. The two most commonly used inducible systems employ doxycycline or mifepristone as the drug activating a silent trans-activator, which is expressed from a constitutive promoter. We evaluated the alterations provoked by constitutive expression in the liver of rtTA2 S -M2 (rtTA2; second-generation reverse tetracycline-controlled trans-activator) and GLp65, which are the trans-activators of the doxycyline-and mifepristone-inducible systems, respectively. To this end we performed transcriptomic analysis of mice expressing these trans-activators in the liver over 1 month. rtTA2 expression induced alterations in a few genes (69 gene probesets; false discovery rate [FDR], ϳ0.05), whereas GLp65 caused more numerous changes (1059 gene probe-sets, an FDR of ϳ0.05). However, only 20 and 53 of the genes from the rtTA2 and GLp65 groups, respectively, showed changes (R-fold Ն 3). Functional assignments indicate that alterations were mild and of little general significance. Few additional transcriptomic changes were observed when expressing trans-activators in the presence of inducer drugs; most were due to the drugs themselves. These results and the absence of toxicity observed in treated animals indicate that the two inducible systems are well tolerated and have little impact on the liver transcriptome profile. The milder alterations found with the use of rtTA2 suggest that this system is possibly safer for gene therapy applications. 1233