The effectiveness of a combined topical and systemic antibiotic regimen was studied in an animal model previously shown to simulate clinical surgical wound infection. At a high level of bacterial contamination, the combination regimen produced a lower infection rate than either a placebo (p < 0.01), a topical antibiotic administered alone (p < 0.01), or a systemic antibiotic administered alone. At a lower level of bacterial contamination, no additional reduction in infection rates was produced by the combination regimen when compared with systemic antibiotic administered alone. These experimental results suggest that when wound contamination is great, a combination of topical and systemic antibiotics is the more effective regimen. Where wound contamination is less severe, systemic antibiotic prophylaxis is all that is required; no further benefit is obtained by the additional administration of topical antibiotics. Clinical trials appear justified to confirm or refute this hypothesis.