Two experiments examined the influence of road characteristics on driver fatigue in a prolonged simulator drive. In experiment one, ten military truck drivers drove a mixed route, with straight, winding, and straight highway segments. In experiment two, 16 additional drivers drove either a straight, a winding, or a mixed route. Fatigue symptoms were assessed using performance, subjective, and psychophysiological measures (HRV). We hypothesized that drivers adopt different fatigue-coping strategies relative to the demands of the drive. Thus, on straight roads drivers are more likely to loosen their driving demands by either increasing their driving speed and/or not maintaining the lane position, as the road is tolerant to both strategies, whereas on winding roads, drivers are more likely to increase their speed but not their lane positioning. Our results confirm that decremental changes in driving performance varied among road types. In the straight road components, we found decrements in the quality of lane maintaining (experiment one) and steering quality (experiments one and two) and longitudinal speed (experiment two). In the winding road, we found that drivers increased their driving speed over time (experiments one and two).