Stress ulcer is clinically prevalent but the underlying mechanisms are not well understood. This study aimed to investigate the role of sympathovagal imbalance in the development of water immersion restraint stress (WRS)-induced gastric mucosal lesion. Wistar rats were subjected to either restraint stress (RS) (N=7) or WRS (N=7) for 5 hours. Linear parameters of heart rate variability (HRV) and Poincare plot were analyzed based on the surface ECGs. Gastric mucosal lesion was evaluated by gross anatomy and histology. Mean RR intervals significantly increased (P<0.001) in a time-dependent manner in the WRS group, but slightly decreased (P<0.001) in the RS group. Root mean square of successive differences (RMSSD) of RR intervals and high frequency norm (HF power normalized by the total frequency power) were significantly higher in the WRS group than the RS group (P<0.001). Low frequency (LF) norm and LF/HF ratio increased significantly one hour after stress and then declined to similar levels in both groups. The Poincare plots of RR intervals in the WRS group shifted right-upwardly and showed dispersed patterns compared with the RS group. Gastric mucosae showed serious hemorrhage, effusion and structural collapse in the WRS group, but remained normal in the RS group. Bilateral cervical vagotomy suppressed the increase of HRV and prevented the gastric mucosal lesion induced by WRS. We conclude that parasympathetic overactivity is the predominant autonomic response to WRS and is most probably the leading mechanism of WRS-induced gastric mucosal lesion in rat.