Objective To assess divided-attention performance when driving under the influence of cannabis with and without alcohol. Three divided-attention tasks were performed following administration of placebo, cannabis, and/or alcohol. Methods Healthy adult cannabis users participated in 6 sessions, receiving combinations of cannabis (placebo/low-THC/high-THC) and alcohol (placebo/active) in randomized order, separated by washout periods of ≥1 week. At 0.5 hours post-dosing, participants performed simulator drives in the University of Iowa National Advanced Driving Simulator (NADS-1), a full vehicle cab simulator with a 360° horizontal field of view and motion base that provides realistic feedback. Drives contained repeated instances of three tasks: a side-mirror task (reaction to a triangle appearing in the side-mirrors), an artist-search task (select a specified artist from a navigable menu on the vehicle’s console), and a message-reading task (read aloud a message displayed on the console). Blood THC and breath alcohol concentration (BrAC) were interpolated using individual power curves from samples collected approximately 0.17, 0.42, 1.4, and 2.3 hours post-dose. Driving measures during tasks were compared to equal-duration control periods occurring just prior to the task. Performance shifts, task completion, and lane departures were modeled relative to blood THC and BrAC using mixed-effects regression models. Results Each 1 µg/L increase in blood THC concentration predicted increased odds of failing to complete the artist-search task (OR: 1.05, 95% CI: 1.01-1.11, p = 0.046), increased odds of selecting at least one incorrect response (OR: 1.05, 95% CI: 1.00-1.09, p = 0.041), declines in speed during the side-mirror task (0.005 m/s, 95% CI: 0.001-0.009, p = 0.023), and longer lane departure durations during the artist-search task (0.74% of task-period, 95% CI: 0.12-1.36 p = 0.020). BrAC (approximately 0.05%) was not associated with task performance, though each 0.01 g/210 L increase predicted longer departure durations during the side-mirror task (1.41% of task-period, 95% CI: 0.08-2.76, p = 0.040) and increased standard deviation of lane position in the message-reading task (0.61 cm, 95% CI: 0.14-1.08, p = 0.011). Conclusions With increasing medical and legal cannabis use, understanding the impact of acute cannabis use on driving performance, including divided-attention, is essential. These data indicate that impaired divided-attention performance is a safety concern.