Although pain and subsequent thrombophlebitis are complications in patients receiving intravenous (IV) diazepam, the mechanism and accompanying histology are unknown. To further elucidate the pathogenesis for this and determine whether it can be minimized, adult female rats received IV diazepam, diazepam vehicle, lidocaine, a combination of lidocaine and diazepam, or N saline solution, and underwent subsequent tissue light microscopy. Vascular tissue from animals receiving IV diazepam alone revealed marked inflammation with inflammatory edema and intramural polymorphonuclear-cell infiltration. Intravascular thrombosis and complete vein-wall destruction were also present in some animals as early as 48 hours after IV diazepam. Diazepam vehicle and diluted diazepam produced similar morphologic alterations. Lidocaine or saline IV resulted in no histologic alterations, while lidocaine added to diazepam did not reduce the inflammatory response. These results represent the first systematic morphologic evaluation of vein response to intravascular diazepam and suggest that it produces rapid and detrimental morphologic alterations. The dilution of diazepam or combination with lidocaine does not appear to alter these findings, and diazepam vehicle appears to assume a role in the production of the vascular injury.