Background: Driving fatigue can have serious consequences. Too often fatal accidents are caused by fatigue. However, it is not uncommon for fatigue to occur while driving when the driver is under-challenged. Due to the increasing automation of vehicles, it is foreseeable that the number of accidents caused by monotony will increase. Interactions between driver and vehicle through gamification can remedy the situation and provide the driver with new stimuli during an otherwise monotonous journey. Methods: In order to test the effectiveness of such interactions, we conducted a driving simulator study with 31 test persons to investigate driving performance and psycho-physiological parameters. Each subject ran through the experiment three times in randomized order to test the interaction system in comparison to a ride in which the driver was alone and a ride in which the driver had a co-driver. Results: The results provide clear indications of safer driving of the test subjects when driving with gamification and with a passenger. The tested interaction system prevents upcoming fatigue in a similar way to communication with a passenger. The experiments also provide insights into the effects of monotony in vehicle driving.