The current manuscript presents the research protocol that has been developed in order to enable the valid transferability of driver simulator results in real traffic conditions. It responds to the weaknesses that have been recognised in the driving simulator validity research field, with respect to the validity of the experimental process being followed as well as to the methodology applied for the comparative analysis of the collected measurements. A case study concerning a semi-dynamic driving simulator is presented. The research hypotheses, the experimental plan and the basic conditions of the analysis methodology that have supported it are described. Trials have been conducted in a semi-dynamic simulator and on-road with 36 drivers (12 trainees, 12 novice and 12 experienced), in “following vehicle” and “free driving” scenarios in highway, rural and urban roads in order to prove the established research hypotheses for a series of driving behaviour metrics.