International travelers are frequently at risk for travelers’ diarrhea (TD) and malaria. Doxycycline was one of the earliest antibiotics shown to have efficacy in TD prevention. With increasing resistance and recommendations against antibiotic chemoprophylaxis, doxycycline fell out of use. We evaluated TD incidence and risk factors in a prospective cohort of travelers, specifically in regard to malaria prophylaxis. Travelers’ diarrhea was defined as 3 3 loose stools in 24 hours or two loose stools in 24 hours associated with other gastrointestinal symptoms. The Poisson regression model with robust error variance was used to estimate the RR of TD. Three thousand two hundred twenty-seven trips were enrolled: 62.1% of participants were male, with a median age of 39 years (interquartile range [IQR] 27,59) and a median travel duration of 19 days (IQR 12,49); 17.4% developed TD; 32% traveled to Africa, 40% to Asia, and 27% to the Caribbean and Latin America; and 20% took doxycycline for malaria chemoprophylaxis, 50% took other antimalarials, and 30% took none. Decreased RR of TD was associated with doxycycline (RR 0.62 [0.47–0.82], P < 0.01) and military travel (RR 0.57 [0.47–0.70], P < 0.01). Increased risk of TD was associated with female gender (RR 1.28 [1.09–1.50], P < 0.01), hotel accommodations (RR 1.30 [1.10–1.53], P < 0.01), travel to tropical South America (RR 1.34 [1.09–1.64], P < 0.01), and duration of travel (RR 1.00 [1.00–1.01], P < 0.01). The use of doxycycline for malaria prophylaxis is associated with lower TD risk, suggesting increasing bacterial enteropathogen susceptibility similar to previous observations. Doxycycline selection for antimalarial chemoprophylaxis may provide additional traveler benefit in infection prevention.