Topical antimicrobial therapy has the potential to limit the mortality and morbidity of contaminated battlefield injuries. Many agents available are ill-suited for use on the battlefield; however, mafenide acetate solution (MAS) has known efficacy as a burn dressing adjunct, and previous work with mafenide as a direct chemotherapeutic has shown promise. A total of 71 male Sprague-Dawley rats underwent a 20% TBSA full-thickness scald. Wounds were inoculated with a solution containing 1 x 10 colony-forming units per milliliter of Pseudomonas aeruginosa 1244 (ATCC 27317). Treatments with 10% mafenide acetate cream (MAC), 5% MAS, 5% mafenide hydrochloride solution (MHS), and 4% chlorhexidine gluconate solution (CHG) were established. Agents were applied directly to the wound daily for 10 days. Animals were monitored for 21 days and euthanized if they manifested a moribund state as a result of sepsis. Survival to study completion in the negative control group (no treatment) was 25% (3/12). Survival in the positive control group (MAC) was 100%. None of the test agent groups demonstrated significant survival over the untreated controls; MAS resulted in 5/12 (42%) survival (P = .67), CHG in 4/12 (33%) survival (P = 1.0), and MHS resulted in 2/12 (17%) survival (P = 1.0). There were no significant differences in group weights on day 1. By day 6, all test agent groups were significantly underweight compared with the MAC group. This trend resolved as underweight animals died. We did not demonstrate significant prevention of wound sepsis with these agents as we used them. These techniques should not be substituted for established burn care. Aqueous direct topical antimicrobial agents have logistical advantages over creams and dressing soaks for field use, and the search for a battlefield-expedient agent for use at or near the point of wounding should continue.