Most routine daily trips take place along the same route, a fact that previous studies have not investigated together with the repeated situation of conflicting with other road users. Conse-quently, our study addresses driver behaviour by separating the driving experience into three categories: (i) drivers unfamiliar with the route, (ii) those route-familiar, and (iii) situation -familiar drivers. The specific case of driver-pedestrian interaction at uncontrolled mid-block crosswalks is investigated. A multi-level factorial experiment including (i) crosswalk design (linear sidewalk and curb extension), (ii) driver familiarity, and (iii) pedestrian time gap acceptance (4, 6, and 8 s) was conducted using a driving simulator. Fifty-two participants were divided into four groups and stratified by age, gender, and driving experience. The minimum instantaneous time to collision, post-encroachment time, maximum car deceleration, and maximum car speed were all used as surrogate safety measures (SSM).Route-familiarity led to higher speed, while situation-familiarity positively affected driving behaviour making drivers more inclined to decrease their speed at circa 100 m before a crosswalk. The curb extension layout enhanced pedestrian safety and mitigated any adverse effects due to familiarity, with a particularly relevant impact on SSM at low accepted time gaps for pedestrians. Situation-and route-familiarity treatment protocols lead to different behaviours among drivers, indicating a clear need to account for these two familiarity levels in experiments on safety-related countermeasures.