In Cusco, Peru, and South America in general, there is a dearth of travelers' diarrhea (TD) data concerning the clinical features associated with enteropathogen-specific infections and destination-specific risk behaviors. Understanding these factors would allow travel medicine providers to tailor interventions to patients' risk profiles and travel destination. To characterize TD etiology, evaluate region-specific TD risk factors, and examine relationships between preventive recommendations and risk-taking behaviors among medium- to long-term travelers' from high-income countries, we conducted this case-case analysis using 7 years of prospective surveillance data from adult travelers' presenting with TD to a physician in Cusco. At the time of enrollment, participants provided a stool sample and answered survey questions about demographics, risk behaviors, and the clinical features of illness. Stool samples were tested for norovirus (NV), bacteria, and parasites using conventional methods. Data obtained were then analyzed using case-case methods. NV (14%), enterotoxigenic Escherichia coli (11%), and Campylobacter (9%), notably ciprofloxacinresistant Campylobacter, were the most frequently identified pathogens among adults with TD. Coinfection with multiple enteropathogens occurred in 5% of cases. NV caused severe disease relative to other TD-associated pathogens identified, confining over 90% of infected individuals to bed. Destination-specific risk factors include consumption of the local beverage chicha, which was associated with Cryptosporidium infection. Preventive interventions, such as vaccines, directed against these pathogens could significantly reduce the burden of TD.