Background: Repair of large ventral hernias with loss of domain can be facilitated by preoperative Botulinum toxin A (BTA) injections and preoperative progressive pneumoperitoneum (PPP). The aim of this study is to evaluate the outcomes of ventral hernioplasty using a standardized algorithm, including component separation techniques, preoperative BTA and PPP. Methods: All patients between June 2014 and August 2018 with giant hernias (either primary or incisional) of more than 12 cm width were treated according to a previously developed standardized algorithm. Retrospective data analysis from a prospectively collected dataset was performed. The primary outcome was closure of the anterior fascia. Secondary outcomes included complications related to the preoperative treatment, postoperative complications, and recurrences. Results: Twenty-three patients were included. Median age was 65 years (range 28–77) and median BMI was 31.4 (range 22.7–38.0 kg/m2). The median loss of domain was 29% (range 12–226%). For the primary and secondary endpoints, 22 patients were analyzed. Primary closure of the anterior fascia was possible in 82% of all patients. After a median follow-up of 19.5 months (range 10–60 months), 3 patients (14%) developed a hernia recurrence and 16 patients (73%) developed 23 surgical site occurrences, most of which were surgical site infections (54.5%). Conclusion: Our algorithm using both anterior or posterior component separation, together with preoperative BTA injections and PPP, achieved an acceptable fascial closure rate. Further studies are needed to explore the individual potential of BTA injections and PPP, and to research whether these methods can prevent the need for component separation, as postoperative wound morbidity remains high in our study.