Background Erectile dysfunction (ED) is a socio‐economic problem, there are several options for its management including Intra‐Cavernosal Injection (ICI). Objective To compare the safety, efficacy, and durability of ICI of Onabotulinum toxin‐A (BTX)in different doses (50 & 100 U) against placebo (saline) in the Management of Vasculogenic ED non‐responding to pharmacological therapy (phosphodiesterase type 5 inhibitors or/and ICI of trimix). Materials and Methods A prospective randomized double‐blind placebo‐controlled trial conducted between July 2016 to February 2019. A total of 176 patients were randomly assigned (1:1:1) to one of the treatment sequences: Botox 100 U group (BTX‐100; 62 patients), Botox 50 U group (BTX‐50; 59 patients) or Placebo group (55 patients). All patients were followed‐up for 6 months. Results Significant improvement in all parameters i.e.; SHIM score & Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), Global Assessment Score (GAS) and Doppler parameters (P < 0.001) was observed in patients of BTX‐100 and BTX‐50 groups with maximum improvement at 3rd month of treatment. Around 40% of patients were responders and abled to engage in sexual intercourse. Patients in placebo group didn’t experience significant improvement (P = 0.264). It was noted that; at the 2nd week and 3rd months after treatment, there was no statistically significant difference in the improvement of these parameters in BTX‐100 & BTX‐50 groups (P >0.05). In the 6th month, there was a statistically significant difference between the aforementioned groups in favor of BTX‐100 (P< 0.01). Conclusions only one‐time ICI of BTX (50 U and 100 U) is effective and safe for the treatment of refractory ED. This agent has a considerable long duration of action particularly BTX‐100U seems to be more durable.