Impaired driving is a significant traffic safety problem, and alcohol and drugs taken before driving contribute substantially to this problem. With the increase in use of prescription medication and the decriminalization of some drugs, it has become increasingly important to understand the manifestation of driver impairment. Building upon previous alcohol research conducted at the National Advanced Driving Simulator (NADS), this study enrolled commercial bus drivers to evaluate the effect of triazolam on driving performance to assess difference between placebo, 0.125, and 0.25 mg doses in a randomized and double-blind design. On each of three randomized visits, subjects drove a simulator scenario that had previously been used to demonstrate effects of alcohol on driving performance. Plasma triazolam levels were obtained before the simulator drive. The protocol included participants receiving study medication and placebo over a 3-week period of time one to two weeks apart. The simulator drives used for this analysis occurred approximately 140 minutes after dosing—after the subjects had completed four bus simulator drives and neuropsychological tests over a 2-hour period of time surrounding dosing. The driving scenario contained representative situations on three types of roadways (urban, freeway, and rural) under nighttime driving conditions. Lane keeping performance (ability to drive straight in the lane) under the three doses of triazolam demonstrates that at the 0.25 mg dose, statistically significant effects on performance are observed, but no effects are found at the 0.125 mg level when testing at this time period after dosing. This differs from the effects of alcohol, which shows impairing effects at a 0.05% blood alcohol concentration (BAC) and a greater effect at 0.10% BAC. These results demonstrate the importance of understanding how different types of drugs affect driving performance in realistic driving environments. Although some compounds may have an effect that correlates linearly to dosage, that is not always the case. An understanding of these differences and how they vary across driving tasks is essential to developing a robust evaluation protocol that can accurately describe the effects of a wide variety of drugs on driver impairment. This information can be used to reduce the risk of deleterious effects of therapeutic medications while ensuring their safe and beneficial use.