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Burkholderia pseudomallei is the causative agent of melioidosis and presents with diverse clinical manifestations. Naturally occurring infection occurs following contamination of cuts or skin abrasions, or ingestion of contaminated water, and occasionally through inhalational of infected soil or water particles. The influence of the route of disease acquisition on the efficacy of medical countermeasures has not been explored in humans or in appropriate animal models. The efficacy of co-trimoxazole against melioidosis acquired by different routes of exposure was assessed in postexposure prophylaxis (PEP) and treatment studies in marmoset models of melioidosis. Following challenge with B. pseudomallei by the inhalational, subcutaneous, or ingestion routes of administration, animals were given co-trimoxazole at 12 hourly intervals for 14 days, starting either 6 h postchallenge or at the onset of fever. Animals were then observed for 28 days. All animals that received antibiotic 6 h postchallenge survived the duration of dosing. All animals that received antibiotics at the onset of fever completed the treatment, but 10%, 57%, and 60% of those with ingestion, subcutaneous, and inhalation challenge relapsed, respectively. Bacteriological and histological differences were observed between placebo-control animals and those that relapsed. Immunological profiles indicate difference between animals given placebo and those that relapsed or survived the duration of the study. A broad T-cell activation was observed in animals that survived. Overall, these data suggest the efficacy of co-trimoxazole, as measured in the incidence of relapse, differs depending on the disease-acquisition route. Therefore, there are implications in treating this disease in regions of endemicity.