Background: The aim of this pilot study is to investigate the impact of virtual reality exposure therapy (VRET) on brain metabolism and connectivity. Eighteen patients with acrophobia were assessed by an F-18-FDG PET scan sensitized by virtual exposure before treatment, and nine of them were assessed again after eight sessions of VRET. Statistical Parametric Mapping was used to study the correlations between metabolism and pretherapeutic clinical scores and to compare metabolism before and after VRET (p voxel < 0.005, corrected for cluster volume). Metabolic connectivity was evaluated through interregional correlation analysis. Results: Before therapy, a positive correlation was found between scores on the behavioural avoidance test and left occipital metabolism (BA17-18). After VRET, patients presented increased metabolism in the left frontal superior gyri and the left precentral gyrus, which showed increased metabolic connectivity with bilateral occipital areas (BA17-18-19), concomitant with clinical recovery. Conclusions: This study highlights the exciting opportunity to use brain PET imaging to investigate metabolism during virtual exposure and reports the involvement of the visual-motor control system in the treatment of acrophobia by VRET.