Long-term resorbable mesh represents a promising technology for complex ventral and incisional hernia repair (VIHR). Preclinical studies indicate that poly-4-hydroxybutyrate (P4HB) resorbable mesh supports strength restoration of the abdominal wall. This study evaluated outcomes of high-risk subjects undergoing VIHR with P4HB mesh. This was a prospective, multi-institutional study of subjects undergoing retrorectus or onlay VIHR. Inclusion criteria were CDC Class I, defect 10–350 cm2, ≤ 3 prior repairs, and ≥ 1 high-risk criteria (obesity (BMI: 30–40 kg/m2), active smoker, COPD, diabetes, immunosuppression, coronary artery disease, chronic corticosteroid use, hypoalbuminemia, advanced age, and renal insufficiency). Physical exam and/or quality of life surveys were performed at regular intervals through 18 months (to date) with longer-term, 36-month follow-up ongoing. One hundred and twenty-one subjects (46M, 75F) with an age of 54.7 ± 12.0 years and BMI of 32.2 ± 4.5 kg/m2(mean ± SD), underwent VIHR. Comorbidities included the following: obesity (n= 95, 78.5%), hypertension (n= 72, 59.5%), cardiovascular disease (n= 42, 34.7%), diabetes (n= 40, 33.1%), COPD (n= 34, 28.1%), malignancy (n= 30, 24.8%), active smoker (n= 28, 23.1%), immunosuppression (n= 10, 8.3%), chronic corticosteroid use (n= 6, 5.0%), advanced age (n= 6, 5.0%), hypoalbuminemia (n= 3, 2.5%), and renal insufficiency (n= 1, 0.8%). Hernia types included the following: primary ventral (n= 17, 14%), primary incisional (n= 54, 45%), recurrent ventral (n= 15, 12%), and recurrent incisional hernia (n= 35, 29%). Defect and mesh size were 115.7 ± 80.6 and 580.9 ± 216.1 cm2(mean ± SD), respectively. Repair types included the following: retrorectus (n= 43, 36%), retrorectus with additional myofascial release (n= 45, 37%), onlay (n= 24, 20%), and onlay with additional myofascial release (n= 8, 7%). 95 (79%) subjects completed 18-month follow-up to date. Postoperative wound infection, seroma requiring intervention, and hernia recurrence occurred in 11 (9%), 7 (6%), and 11 (9%) subjects, respectively. High-risk VIHR with P4HB mesh demonstrated positive outcomes and low incidence of hernia recurrence at 18 months. Longer-term 36-month follow-up is ongoing.