Background The aim of this study was to analyze the risk factors for vasovagal reaction (VVR) in manual femoral sheath removal after percutaneous coronary intervention and to discuss methods for the prevention and control of VVR. Methods The data of 455 patients who underwent percutaneous intervention in four interventional centers during a period of 30 months were retrospectively analyzed. Patients were divided into a VVR group and a control group according to whether VVR developed. The clinical data of all patients were analyzed using univariate and multivariate logistic regression analysis to examine VVR -related factors. Results A total of 455 patients underwent 464 manual femoral sheath removal operations, of whom 12 developed VVR (2.59%). Of these 12 VVR patients, one had VVR during and 11 had VVR after the intervention. There were no statistically significant differences between the two groups in age, body mass index, gender, time of sheath removal, proportions of patients with hypertension, diabetes, and hyperlipemia, laboratory values of hemoglobin a1c, and ejection fraction (p & x202f;> 0.05). Compared with the control group, use of nitrates was the only risk factor with a significant correlation with VVR (p & x202f;= 0.012). Conclusion In manual femoral sheath removal, the use of nitrates is the most important risk factor for the occurrence of VVR after percutaneous intervention.