Objective To assess driving performance and neurocognitive skills of long-term users of sedating antidepressants, in comparison to healthy controls. Methods Thirty-eight long-term (>6 months) users of amitriptyline (n= 13) and mirtazapine (n= 25) were compared to 65 healthy controls. Driving performance was assessed using a 1-h standardised highway driving test in actual traffic, with road-tracking error (standard deviation of lateral position [SDLP]) being the primary measure. Secondary measures included neurocognitive tasks related to driving. Performance differences between groups were compared to those of blood alcohol concentrations of 0.5 mg/ml to determine clinical relevance. Results Compared to controls, mean increase in SDLP of all antidepressant users was not significant, nor clinically relevant (+0.75 cm, 95% CI: -0.83 cm; +2.33 cm). However, users treated less than 3 years (n= 20) did show a significant and clinically relevant increase in SDLP (+2.05 cm). No significant effects were observed on neurocognitive tasks for any user group, although large individual differences were present. Most results from neurocognitive tests were inconclusive, while a few parameters confirmed non-inferiority for users treated longer than 3 years. Conclusion The impairing effects of antidepressant treatment on driving performance and neurocognition mitigate over time following long-term use of 3 years.