Objectives: Efficacy of postoperative Povidone-Iodine prophylaxis and surgical site infection in appendectomy surgery. Study Design: Randomized clinical trial. Place and Duration: Department of Surgery, Liaquat University Hospital Jamshoro/Hyderabad from March 2016 to November 2017. Subjects and Methods: Diagnosed cases of acute appendicitis with classical clinical presentation were included in the study protocol. 60 patients were those, who were applied 1% povidone-iodine solution (cases) to wound post operatively versus 60 patients (control) were those in whom wound not irrigated with Povidone- Iodine. Ethical approval and consent were taken. Data was noted in a proforma and analyzed on SPSS 22.0 (P≤0.05). Results: Age (mean ± SD) in control and cases was observed as 25.5 ± 8.5 and 24.5 ± 9.5 years respectively (P=0.76). Male and female were noted as 43 (%) and 17 (%) & 45 (%) and 15 (%) in control and cases respectively (P >0.05). Wound healing score by Southampton classification of wound healing shows lesser frequency of surgical site infection in cases compared to controls (P <0.05). Grade 4 pus discharging wound infection was noted in 2 (3.33%) control versus 3 (5.0%) in cases (P=0.021). Conclusion: It is concluded that the 1% Povidone- Iodine solution is effective in preventing the post appendectomy surgical site infection.