PDE-5 inhibitor counterfeit drugs have been increasingly adulterated in supplement diets and widely distributed through internet markets and underground routes. In this study, GC-MS/MS method was developed for the screening and confirmation of 63 erectile dysfunction drugs in supplements. The trimetylsilyl (TMS) derivatization of PDE-5 inhibitors produced the characteristic fragments within similar structural moiety for sildenafil, tadalafil, and vardenafil analogues. Specific common fragments enabling to reflect their structural characteristics were observed as m/z 383, 384, and 265 for sildenafil analogues, m/z 334 and 241 for tadalafil analogues, and m/z 476, 384, for vardenafil analogues. These ions were formed through the cleavage of piperazinosulfonamide or piperazine ring for sildenafil and vardenafil analogues, and the successive losses of benzodioxole and diketopiperazine for tadalafil analogues. For the rapid screening of multiple classes of the PDE-5 inhibitor adulterants, extracted common ion chromatograms (ECICs) based on specific fragments of similar molecular moieties were attempted. These ECICs of specific ions could effectively cover PDE-5 inhibitor adulterants and new emerging counterfeit drugs. Especially, selected reaction monitoring (SRM) mode in GC-MS/MS could offer high sensitivity and selectivity for erectile dysfunction drugs derivatives in complicate matrix samples. The established method was successfully applied for the monitoring of several types of dietary supplements to protection of public health and consumer safety.