Background Contaminated operative fields pose significant challenges for surgeons performing ventral hernia repair. Although biologic meshes have been utilized increasingly in these fields, recent evidence suggests that synthetic meshes represent a viable option. We analyzed the outcomes of biologic and synthetic mesh utilized in patients undergoing major ventral hernia repair in clean-contaminated/contaminated fields. Methods We conducted a multicenter, retrospective review of patients undergoing open ventral hernia repair in clean-contaminated/contaminated fields using biologic or synthetic mesh. Patient and hernia details were characterized. Primary outcomes included 90-day surgical site event, surgical site infection, and hernia recurrence. Results A total of 126 patients undergoing major ventral hernia repair in clean-contaminated/contaminated fields (69 biologic and 57 synthetic meshes) were analyzed. Groups were similar in both patient and hernia characteristics. There were 13 (22.8%) surgical site events in the synthetic cohort compared to 29 (42.0%) in the biologic cohort, P = .024. Similarly, surgical site infections were less frequent in the synthetic group, with 7 (12.3%) vs 22 (31.9%), P = .01. With a mean follow-up of 20 months, there were more recurrences in the biologic group: 15 (26.3%) vs 4 (8.9%) in the synthetic group, P = .039. Conclusion The choice of mesh for clean-contaminated/contaminated ventral hernia repair remains debatable. We demonstrated that using synthetic sublay mesh resulted in a significantly lower wound morbidity and more durable outcomes versus a similar cohort of biologic repairs. This is likely secondary to improved bacterial clearance and faster integration of macroporous synthetics. Overall, our findings not only support suitability of synthetic mesh in contaminated settings but also challenge the purported advantage of biologics in clean-contaminated/contaminated ventral hernia repairs.