Intracavernosal injections of botulinum toxin A (BTX/Aic) may be effective for difficult-to-treat erectile dysfunction (ED). This is a retrospective case series study of the effectiveness of repeated off-label BTX/Aic(onabotulinumtoxinA 100U, incobotulinumtoxinA 100U or abobotulinumtoxinA 500U) in men with ED and insufficient response to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandinE1 intracavernosal injections (PGE1 ICIs), defined as an International Index of Erectile Function-Erectile Function domain score (IIEF-EF) < 26 on treatment. Further injections were performed on patients’ requests, and the files of men who underwent at least two injections were reviewed. The response to BTX/Aicwas defined as the achievement of the minimally clinically important difference in IIEF-EF adjusted to the severity of ED on treatment at baseline. Out of 216 men treated with BTX/Aicand PDE5-Is or PGE1-ICIs, 92 (42.6%) requested at least a second injection. The median time since the preceding injection was 8.7 months. In total, 85, 44 and 23 men received, respectively, two, three and four BTX/Aic. The overall response rate was 77.5%: 85.7% in men with mild ED, 79% for moderate ED and 64.3% for severe ED on treatment. The response increased with repeated injections: 67.5%, 87.5% and 94.7%, respectively, after the second, third and fourth injections. Post-injection changes in IIEF-EF were similar across injections. The time from injection to request for a further injection varied little. Four men reported penile pain at the time of injection (1.5% of all injections), and one experienced a burn at the penile crus. Repeated BTX/A injections combined with PDE5-Is or PGE1-ICIs produced an effective and durable response, with acceptable safety.