Background: In infected incisional ventral hernias (IVHs), the use of a synthetic non-absorbable mesh is not recommended and biological meshes hold promise. However, the level of evidence for their safety and efficacy remains low. Methods: The SIMBIOSE trial is a multicenter, phase III, randomized, controlled trial comparing the use of a biological mesh versus traditional wound care in patients with an IVH. The primary end point is 6-month infectious and/or wound morbidity. Secondary end points are wound infection and recurrent hernia rates, post-operative pain, quality of life, time to heal, reoperation need, impact of the cross-linked mesh structure, and a medico-economic evaluation. One hundred patients need to be included. Results: The main results expected with biological mesh use are a significant decrease of post-operative morbidity, hernia recurrence, time to heal, and costs with an improved quality of life. Conclusions: For the first time, the impact of biological meshes in the treatment of IVHs will be evaluated in an academic, randomized, phase III trial to provide scientific evidence (NCT01594450).