Background Patients with schizophrenia (SZ) present a higher level of cardiovascular morbidity than the general population due to poor physical tness and a sedentary lifestyle. Moreover, despite major therapeutic advances in the management of SZ, some clinical symptoms remain resistant to pharmacological approaches. A large number of studies support the effectiveness of physical activity (PA) for both physical and mental health in SZ. The main objective of the present study is to assess the effects of a remote, web-based adapted PA program (e-APA) compared to a health education program (e-HE) on brain plasticity in SZ and healthy volunteers (HV). The secondary objectives are to assess the effects of e-APA on other cerebral variables as well as clinical, neurocognitive, circadian, biological, and physiological variables. Methods: The study is an interventional, multicenter, randomized open-label controlled trial. Forty-two SZ will be randomized to either the active group (e-APA, N = 21) or non-active group (e-HE, N = 21), and 42 HV will be matched to SZ according to age, gender, and level of PA. Interventions will consist of 32 sessions (2x60 minutes/week, for 16 weeks) via supervised home-based videoconferencing. The active group will carry out an individualized PA program of moderate to vigorous intensity. Pre-and post-intervention cerebral magnetic resonance imaging (MRI) will be performed to evaluate changes in global hippocampal volume. Other cerebral assessments using diffusion tensor imaging, arterial spin labelling, spectroscopy and resting-state functional MRI will be performed. In addition, clinical, neurocognitive and circadian rhythms assessments as well as physical tests and biological analyses will be conducted. Discussion: To our knowledge, this is the rst study aiming to evaluate the e cacy of APA delivered by supervised home-based videoconferencing in SZ. Moreover, using multimodal MRI, this study could clarify the pathophysiological mechanisms underlying the e cacy of APA. Finally, this innovative approach (remote, web-based APA) might also increase participation in long-term PA since PA-based programs are known to have low adherence and early dropout. The results of this study should promote the inclusion of PA interventions as a novel adjunctive therapy for SZ. Trial registration: ClinicalTrials.gov identi er: NCT03261817. Registered on