Liquid intraurethral prostaglandin E₁ (PGE₁) delivery system was developed using self-microemulsifying drug delivery system (SMEDDS). For this, pseudo-ternary phase diagrams were constructed and characterized. The viscosity of optimized formulation was increased gradually upon the addition of water and it was decreased from the water contents over 40%. With excessive mass of water, the present system transformed to a free flowing microemulsion. These results demonstrate that the present liquid PGE₁ SMEDDS formulation might stay in the urethra as a viscous sol or gel state with contacting the moisture of urethra and easily eliminated by urination. Draize test and long-term stability study revealed that the present system would be safe and PGE₁ would be stable for more than one year at 4 °C, respectively. In the feline animal model, SMEDDS formulation was as effective as PGE₁ intracavernosal injections in terms of ICP (intracavernosal pressure), penile length increment, and erection sustaining time was more elongated than PGE₁ injections. Therefore, SMEDDS was considered as a promising PGE₁ intraurethral liquid formulation for erectile dysfunction treatment.