Abstract Introduction Although the phosphodiesterase 5 inhibitors (PDE5i) are the first-line oral agents for erectile dysfunction (ED) treatment, there is growing number of PDE5i- non responder patients. Management of those patients is challenging and one of the new suggested regenerative therapies is the hyperbaric oxygen therapy (HBOT). HBOT is the application of oxygen under pressure to increase tissue oxygen levels. Few clinical reports were published about HBOT and ED. Objective To evaluate the efficacy and safety of HBOT in sildenafil citrate non- responder organic ED patients. Methods The current study included 30 sildenafil citrate non-responder ED patients. Patients were divided into two groups (randomly assigned and comparably cross-matched for age). Both patients and the investigators were blinded as regards the treatment until the end of the study. Group 1: Patients assigned to the HBOT group (20 patients) were treated with (30) sessions in 5 days/week (90 minutes of 100% oxygen at 2.2 ATA); Group 2: Patients assigned to the control group (10 patients) were exposed to (30) sessions of air oxygen tension at 1 ATA with room oxygen. Baseline laboratory investigations were done (random blood sugar, lipid profile, total & free testosterone). All patients were evaluated with the sexual health inventory for men (SHIM), erection hardness score (EHS), the sexual health encounter profile (SEP), and penile color Doppler initially, at 1 & 3 months after the end of treatment. Results The age mean ± SD in the HBOT group was 56.35±7.43 years and in the control group was 61.7±7.14 years. The current study showed that sildenafil citrate non-responders ED patients with 30 sessions of HBOT in 5 days/week, demonstrated a significant improvement of the total SHIM score, EHS, and SEP after 1 month of stoppage of treatment as compared to the control group. Also, penile color Doppler evaluation showed a significant improvement of 10 &20 minutes peak systolic velocity (PSV) between patients receiving HBOT compared to the control after 1 month of stoppage of treatment. More interestingly, the improvement of the total SHIM score, EHS, and SEP continued after 3 months of stoppage of the HBOT treatment as compared to the baseline evaluation. In addition, 10 &20 minutes PSV with penile color Doppler evaluation demonstrated maintained improvement after 3 months of stoppage of the HBOT treatment as compared to the baseline evaluation. In addition, the linear regression analysis was done for factors affecting SHIM score improvement (1 month/baseline) in the HBOT treatment group, revealing that hypertension was an independent predictor for SHIM score improvement. Hypertensive patients showed 4.6 times more SHIM score improvement as compared to non-hypertensive patients. As regards HBOT safety, there was no significant difference in adverse effects between the HBOT treatment group and the control group. Conclusions HBOT might be a potential therapeutic modality for sildenafil citrate non-responder ED patients especially in hypertensive patients with good safety profile. Further a multi-centric trial with a larger sample size and a longer follow-up period is recommended. Disclosure No.