Abstract Background Patients requiring ventral hernia (VH) repair during perioperative chemotherapy have a higher risk for post-operative complications. The aim of the study was to perform a case-controlled analysis in patients undergoing chemotherapy who underwent VH repair using biological mesh or synthetic mesh. Methods From January 2013 to December 2015, 32 patients, within 8 weeks from chemotherapy administration, were treated electively for VH repair using a biological mesh (BIOMESH). A control group (CG) receiving chemotherapy within the same time interval and treated with synthetic meshes was selected. There were no differences regarding sex, age, American Society of Anesthesiologists (ASA) score III, BMI, and size of the defect. Morbidity, type of complications, and recurrence rate were investigated and compared between the two groups. Results In the BIOMESH group, eight patients (25 %) experienced complications. Wound dehiscence occurred in four (12.5 %) patients and was treated conservatively. Only three small seromas not requiring treatment were observed. The CG presented a higher mean Clavien-Dindo complication grade (1.94 ± 0.44 vs 1.63 ± 0.52; p = 0.13) and a higher incidence of wound dehiscence ( n = 9/32, 28.1 % vs n = 4/32, 12.5 %; p = 0.11). Five patients developed seroma treated by wound drainage. One patient experienced an intra-abdominal collection treated by percutaneous drainage. At the univariate and multivariate analysis use of traditional mesh, BMI and the ASA III were predictive factors of post-operative complications. Two patients (6.3 %) developed a VH recurrence only in the CG. Conclusions Biological meshes could be considered a valid option to improve post-operative short-term outcomes in selected high-risk patients undergoing chemotherapy treated for VH repair.