First-generation adenovirus (Ad) gene therapy vectors deleted for the E1A, E1B, and E3 regions and carrying foreign genes under the control of strong foreign promoters induce high-level innate inflammatory responses within the first 24 hrs after transduction. Both uptake of the capsid and expression of gene products encoded by the vector contribute to the innate inflammatory response. Natural infections by Ad are frequently asymptomatic, suggesting that Ad has potent methods of inhibiting inflammation. The inability of Ad vectors to counter inflammatory responses suggests that the products of the Ad genes deleted in vector construction play critical roles in inhibiting these responses. Genetic analysis of the roles of Ad early region gene functions in vivo demonstrated that a virus made replication-incompetent by deletion of the preterminal protein gene and deleted for the transcriptional activation function of E1A effectively inhibits the innate inflammatory processes induced by Ad vectors. The mechanism(s) by which the Ad early region proteins inhibit inflammation is complex, as certain early region proteins can promote as well as inhibit inflammation, depending on the genetic context of the virus. Understanding of the roles of the Ad gene products in the induction and inhibition of innate inflammatory functions offers potential for the development of non-inflammatory vectors as well as for understanding of the mechanisms by which inflammation is regulated.