An increasing number of bacteria are resistant to multiple systemic antibiotics. The purpose of this study was to determine if topical antimicrobials are still effective against multi-drug resistant organisms (MDROs). MDROs, including Acinetobacter, Pseudomonas, Klebsiella, Staphylococcus, and Enterococcus, were collected from four burn hospitals. The sensitivity of 47 MDROs to 11 commonly used topical agents (mafenide acetate, nystatin, mafenide + nystatin, silver nitrate, Dakin’s, polymyxin B, neomycin, polymyxin + neomycin, silver sulfadiazine, bacitracin, silver sulfadiazine + bacitracin) was tested using the agar well diffusion assay and compared with the sensitivity of 27 non-MDROs of similar genera. Overall 88% of the tests of the non-MDROs showed susceptibility to the topicals compared with 80% for the MDROs (P < .05). Specific findings included: all of the gram-positive non-MDROs were sensitive to bacitracin compared with only 67% of the MDROs (P < .05); 74% of the non-MDROs were sensitive to neomycin vs 26% of the MDROs (P < .01). Even for the susceptible isolates, the zones of inhibition were smaller for the MDROs than for the non-MDROs (P < .002), indicating decreased susceptibility of the MDROs. Specifically, while the MDRO Acinetobacter were sensitive to most of the topicals, the zones of inhibition for silvadene, silvadene + bacitracin, neomycin, and neomycin + polymyxin were significantly smaller (P < .001) for the Acinetobacter MDROs than the non-MDROs. Although many topicals are still effective against some MDROs, MDROs are more resistant to topicals than are non-MDROs. Some treatment assumptions based historically on the efficacy of topical antimicrobial agents against non-MDROs need to be re-evaluated for MDROs.