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. Consequently, 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.