Background: Erectile dysfunction (ED) is a worldwide health problem causing significant impact on the quality of life of men and their partners. The etiology of ED may be organic, psychogenic or mixed. There were many treatment options for ED, but oral phosphodiesterase type 5 inhibitors are considered the first line of treatment with considerable therapeutic failure rate. Phosphodiesterase type 5 inhibitors therapeutic failure is considered a treatment challenge. Many modalities to overcome phosphodiesterase inhibitors failure or no response had been developed. Objective: To evaluate the efficacy of aspirin when combined with phosphodiesterase inhibitors in erectile dysfunction phosphodiesterase non-responders patients. Patients and methods: The current study was carried out on 40 patients with ED that did not respond to on demand phosphodiesterase inhibitors. Patients were recruited from outpatient clinic of Dermatology, Venerology and Andrology Department, Faculty of Medicine, Al-Azhar University Hospitals from December 2019 to October 2020. A regimen of sildenafil on demand and tadalafil daily for 6 weeks to overcome the phosphodiesterase inhibitors type 5 non response. All the studied patients received 100 mg aspirin daily combined with sildenafil and tadalafil for another 6 weeks to evaluate the effect of adding aspirin on the ED status of the patients. The patients were evaluated using a 5-items version of the International Index of Erectile Function (IIEF-5). Results: The results revealed non-significant improvement after added aspirin to sildenafil and tadalafil in comparison to the same studied group taking sildenafil and tadalafil only. The evaluation was done using a 5-items version of the International Index of Erectile Function (IIEF-5). Conclusion: aspirin combination with PDE5i added no more efficacy than PDE5i alone in ED PDE5i non-responders patients.