Objective: The objective of this study was to evaluate users’ driving performances with a Power Wheelchair (PWC) driving simulator in comparison to the same driving task in real conditions with a standard power wheelchair. Methods: Three driving circuits of progressive difficulty levels (C1, C2, C3) that were elaborated to assess the driving performances with PWC in indoor situations, were used in this study. These circuits have been modeled in a 3D Virtual Environment to replicate the three driving task scenarios in Virtual Reality (VR). Users were asked to complete the three circuits with respect to two testing conditions during three successive sessions, i.e. in VR and on a real circuit (R). During each session, users completed the two conditions. Driving performances were evaluated using the number of collisions and time to complete the circuit. In addition, driving ability by Wheelchair Skill Test (WST) and mental load were assessed in both conditions. Cybersickness, user satisfaction and sense of presence were measured in VR. The conditions R and VR were randomized. Results: Thirty-one participants with neurological disorders and expert wheelchair drivers were included in the study. The driving performances between VR and R conditions were statistically different for the C3 circuit but were not statistically different for the two easiest circuits C1 and C2. The results of the WST was not statistically different in C1, C2 and C3. The mental load was higher in VR than in R condition. The general sense of presence was reported as acceptable (mean value of 4.6 out of 6) for all the participants, and the cybersickness was reported as acceptable (SSQ mean value of 4.25 on the three circuits in VR condition). Conclusion: Driving performances were statistically different in the most complicated circuit C3 with an increased number of collisions in VR, but were not statistically different for the two easiest circuits C1 and C2 in R and VR conditions. In addition, there were no significant adverse effects such as cybersickness. The results show the value of the simulator for driving training applications. Still, the mental load was higher in VR than in R condition, thus mitigating the potential for use with people with cognitive disorders. Further studies should be conducted to assess the quality of skill transfer for novice drivers from the simulator to the real world. Trial registration Ethical approval n 2019-A001306-51 from Comité de Protection des Personnes Sud Mediterranée IV. Trial registered the 19/11/2019 on ClinicalTrials.gov in ID: NCT04171973.