Background <p>Cesarean section (CS) is a lifesaving procedure, yet its rising global use raises concern about adverse maternal outcomes. Although a substantial body of evidence suggests that prior cesarean delivery is associated with an increased risk of intraoperative and postoperative complications, including surgical site infections (SSI), data from prospective comparative cohort studies remain limited. This study was therefore conducted to examine this association and generate evidence to inform context-appropriate preventive strategies and maternal health interventions in low-resource settings such as Ethiopia.</p> Objective <p>To determine and compare the incidence of post-cesarean surgical site infections and maternal outcomes between women undergoing repeat cesarean section (≥ 1 prior cesarean) and those undergoing their first cesarean section.</p> Methods <p>A multicenter prospective cohort study was conducted from January 1 to December 31, 2022, among 1,506 women undergoing cesarean section at three public hospitals: Arba Minch General Hospital (AMGH), Wolayita Sodo University Teaching and Referral Hospital (WSUTH), and Gidole Primary Hospital (GPH) in southern Ethiopia. A total of 753 study participants were systematically sampled and enrolled into each of the exposure cohort (women with ≥ 1 prior cesarean section) and control cohort (first-time cesarean section delivery) in a 1:1 ratio. All participants were followed postoperatively up to 30 days, and patients were monitored for the development of surgical site infections (primary outcome). Additionally, the microbial profile and intraoperative and postoperative maternal complications were assessed as secondary outcomes. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25. The association between repeated cesarean section and surgical site infections was determined by Poisson regression and robust variance estimators. Effect size was reported using both unadjusted Relative Risk (RR) and adjusted Relative Risk (aRR) with a 95% confidence interval <i>(CI</i>). <i>A p-value</i> <i>≤</i> 0.05 was considered statistically significant.</p> Results <p>Overall surgical site infection incidence was 13.5% (95% CI: 11.9–15.4). Women in the repeat cesarean section group had a higher surgical site infection incidence than those in the first-time cesarean section group (20.3% vs. 6.8%), reflecting nearly a threefold increased risk (aRR = 2.94, 95% CI: 2.20–3.93; <i>p</i> &lt; 0.001). Women undergoing repeat cesarean section had a higher proportion of deep incisional infections (30.1% vs. 9.8%) and monobacterial Gram-negative infections (52.9% vs. 31.7%). In this group, operations were longer (59 vs. 40&#xa0;min; <i>p</i> &lt; 0.001), and postoperative hospital stays were extended (3.8 vs. 1.3 days; <i>p</i> &lt; 0.001). They also had higher likelihoods of receiving postoperative antibiotics (RR = 1.65, 95% CI: 1.57–1.75), experiencing intraoperative bleeding or requiring blood transfusion (RR = 1.71, 95% CI: 1.43–2.06), and encountering dense adhesions (RR = 12.0, 95% CI: 3.7–38.4<i>).</i> After adjustment for maternal age, BMI, comorbidity, parity, urgency of surgery, preoperative skin preparation, and hospital type as a priori confounders repeat cesarean section remained strongly associated with outcomes.</p> Conclusion <p>This study observed a higher incidence of surgical site infection (SSI) and other intraoperative complications among women undergoing repeat cesarean section compared with those having a primary cesarean section. These findings underscore the importance of careful perioperative, intraoperative, and postoperative assessment, monitoring, and context-appropriate interventions in resource-limited settings. Further evidence from large controlled trials is recommended to confirm these associations and guide effective preventive strategies.</p>