Objective: A surface-enhanced Raman spectroscopy (SERS) method was developed for non-targeted screening of PDE-5 inhibitors in health wine. Methods: An appropriate SERS base of colloidal gold was prepared, and SERS analysis was conducted after the base was mixed with 78 kinds of PDE-5 inhibitors. The spectrogram screening database was established, and whether the matching degree was higher than 70% was used as the basis for judging whether the PDE-5 inhibitors were suspected to be added. Finally, the sensitivity and specificity of the method were investigated. Results: The best method of preparing PDE-5 inhibitors of SERS base was adding 1.0 mL 1% chlorauric acid and 0.7 mL 1% trisodium citrate into 98.3 mL ultrapure water. The lowest concentrations were sildenafil 0.05 mg/L, tadanafil 0.5 mg/L, thiosildenafil 0.05 mg/L and acevardenafil 0.1 mg/L, respectively. The qualitative results of simulated samples were consistent with those of HPLC-MS. Conclusion: In theory, this method can be used to screen non-targeted illegal addition of PDE-5 inhibitors in health wine.