Objective: Medical management of nonre-constructible and failed reconstruction in patients with peripheral arterial disease (PAD) has limited options. The objective was to study the safety and efficacy of Alprostin in the management of patients presenting with Stages III and IV PAD. We hypothesized that administration of Alprostin will lead to an increase in the transcutaneous oximetry (TcPO2) and ankle-brachial index (ABI) values. It may also aid in decreasing limb pain, promote ulcer healing, and increase claudication distance. Materials and Methods: A retrospective study comprising 60 patients who had presented to vascular surgery with clinical features of PAD. According to the Fontaine's staging criteria, only those patients who had presented with Stages III and IV were included in the study. Patients with critical limb ischemia and nonre-constructible or failed vascular reconstruction disease, who had not improved with conservative management, and patients presenting with Stages III and IV PAD were given injection Alprostin. A total of 6 cycles (each cycle for 3 days, every month) of Alprostin were given, dose being 166.66 mcg over 5 h/day. A qualitative assessment was performed, assessing change in rest pain, claudication distance, ulcer healing, and development of complications. In addition, a quantitative assessment was performed by measuring the TcPO2 and ABI before and after the administration of Alprostin. Results: The study comprised 60 patients, out of whom 55 were male and 5 were female with a mean age of 48.98. The patients were then classified according to the Fontaine Staging, where 50 patients presented with Stage III and 10 patients presented with Stage IV PAD. After the administration of Alprostin, 100% of patients reported of decrease in pain in lower limb, 70% reported of ulcer healing, 55% reported of increase in claudication distance, and complications were only seen in 5% of the patients. TcPO2 values showed a significant rise after the administration of Alprostin, with P value being 0.001. Finally, ABI values also showed a significant improvement after the administration of Alprostin, with P value being 0.001. Conclusion: PAD is a common circulatory condition in which the narrowed arteries in the limbs reduce blood flow to the extremities, most common being lower limbs. There are several lifestyle modifications that can be made to control PAD. Alprostin is a prostaglandin E1 analog, which acts a vasodilator and inhibits platelet aggregation. It helps to reduce vascular cell adhesion molecule levels in circulation, reduces vascular inflammation, promotes ulcer healing, increases claudication distance, and reduces rate of amputation of the affected limb. Hence, it can be concluded that Alprostin has been shown to be a safe and effective drug in patients with nonre-constructible PAD.