BACKGROUND: Erectile dysfunction (ED) is a common disorder that significantly impacts quality of life, and phosphodiesterase type 5 inhibitors (PDE5is) such as tadalafil are one of the primary treatments. However, some patients remain unresponsive, necessitating further investigation. OBJECTIVE: To investigate the association between systemic inflammatory response index (SIRI) and tadalafil unresponsiveness in erectile dysfunction patients. METHODS: A total of 106 male patients who applied to the Andrology outpatient clinic with ED complaints between January and June 2024 were included in the study. Patients were started on daily tadalafil 5 mg therapy, and response was assessed after one month using the International Index of Erectile Function Erectile Function domain (IIEF-EF). SIRI values, calculated using neutrophil, monocyte, and lymphocyte counts, were compared between tadalafil-responsive and unresponsive groups. RESULTS: Tadalafil unresponsiveness was observed in 48.1% of patients. Non-responders had significantly higher mean age(57.44 ± 12.52 vs. 47.22 ± 11.49, CONCLUSION: Findings suggest that systemic inflammation plays a key role in ED pathophysiology and may impair PDE5i efficacy.