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Background Rifamycin SV is under development for treatment of travelers' diarrhea ( TD) in a new oral formulation, Rifamycin SV MMX® ( RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug. Methods This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo ( n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool ( TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration ( MIC), and adverse events (AEs). Results TLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections ( p = 0.0035) with nonsignificant activity against invasive bacteria ( p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance ( p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%). Conclusions RIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon. [ABSTRACT FROM AUTHOR]