Surgical site infections (SSI) are common complications after open ventral hernia repair (OVHR), potentially requiring further intervention. Antibiotic lavage before abdominal closure has been shown to lower the incidence in intra-abdominal and soft tissue SSI. A retrospective review of OVHR was performed with mesh at Greenville Health System Hernia Center between 2008 and 2017. Patients were divided into three groups, receiving no antibiotic irrigation (Grp 1, n = 260), gentamicin alone (Grp 2, n = 263), or gentamicin + clindamycin (G + C) irrigation (Grp 3, n = 299). Differences in categorical variables among the three groups were tested using chi-squared or Fischer's exact test (for n < 5). Analysis of continuous variables was performed using analysis of variance or Kruskal-Wallis test for differences in length of stay. Logistic regression was performed using all clinically relevant variables to determine the effects of irrigation on SSI. Incidence of surgical site occurrence was significantly lower after G + C irrigation (Grp 1, 28.1%; Grp 2, 35.4%; Grp 3, 19.7%; P < 0.001). Incidence of SSI was significantly lower after G + C irrigation, but not G alone (Grp 1, 16.5%; Grp 2, 15.2%; and Grp 3, 5.4%; P < 0.001). Multivariate logistic regression demonstrated significantly increased SSI with contaminated wounds (OR 2.96; 95% confidence interval (CI) 1.39-6.21), dirty wounds (OR 3.84; 95% CI 1.49-9.69), and chronic obstructive pulmonary disease (OR 3.70; 95% CI 2.16-6.38), as expected. Use of G + C was an independent predictor of decreased SSI (OR 0.33; 95% CI 0.16-0.67). Irrigation with a combined G + C antibiotic irrigation significantly reduces the incidence of surgical site infection after OVHR with mesh.