Background <p>Postpartum hemorrhage (PPH) is one of the leading causes of maternal morbidity and mortality worldwide. Intrauterine hemostatic devices are recommended when PPH does not respond to medical treatment. The objective of this study was to assess the factors leading to unsuccessful intrauterine therapy with a chitosan-covered tamponade (CT) for the treatment of PPH and to evaluate clinical outcomes based on real-world data.</p> Methods <p>This registry-based cohort study included all women treated with CT for PPH between January 2017 and June 2022 at a university clinic’s perinatal department. The endpoint was defined as the failure of CT, indicated by the requirement of further invasive procedures for ongoing hemorrhage after CT application. Medical records were reviewed and binary logistic regressions used to evaluate delivery mode, placenta previa, and placenta accreta spectrum as potential risk factors for CT treatment failure.</p> Results <p>The cohort consisted of 230 women, with successful CT treatment in 91.3%. The success rate for mild PPH was 100.0%, for moderate 95.5%, and for severe 84.2%. Five hysterectomies were performed in total. Placenta previa in cesarean sections was identified as the primary risk factor for CT treatment failure, increasing the odds about 7.5-fold (Odds Ratio: 7.48; 95% CI: 1.87–33.15) compared to cesarean sections without placenta previa. Furthermore, delays in CT insertion may also contribute to treatment failure.</p> Conclusion <p>CT serves as an intrauterine treatment for medically intractable PPH. Placenta previa significantly increases the risk of CT treatment failure in cesarean sections. Obstetricians should be particularly vigilant in managing patients with placenta previa and consider early use of CT or a combination of procedures.</p> Trial registration <p>This study was approved by the local Ethics Committee on 11/10/2021 (EA4/231/21).</p>