Objective To investigate the value of inferior vena cava (IVC) respiratory variation to predict fluid responsiveness in spontaneously breathing children following craniosynostosis surgery. Methods Children who scheduled for craniosynostosis surgery under general anesthesia were included and transferred to the postanesthesia care unit (PACU) after extubation. The patients in PACU received postoperative sedation and analgesic management. HR, MAP were measured before and after volume expansion (VE) of 5 ml/kg sodium acetate Ringer’s injection within 10 min. At the same time, IVC respiratory variation during spontaneous breathing called inferior vena cava collapsibility index (cIVC) and cardiac output (CO) were measured and calculated by transthoracic echocardiography (TTE). The gold standard for evaluating fluid responsiveness was CO≥10%, and all patients were divided into the responder group (R) and non-responder group (NR). Results A total of 42 children were included. There were 23 volume responders and 19 non-responders. HR and cIVC were decreased and MAP and CO were increased in group R after VE (p 0.05). cIVC was higher in group R than in group NR before VE (p 0.05). Areas under the ROC curves of cIVC was 0.827 (95% CI: 0.679-0.926) and the cut-off value was 35.6% with a sensitivity of 0.74 and a specificity of 0.84. Conclusions With full sedation and analgesic management, IVC respiratory variation is validated in predicting fluid responsiveness in spontaneously breathing children following craniosynostosis surgery.