Background: In the United States, an estimated 9.4 million foodborne related illnesses from known pathogens and 38.4 million foodborne related illnesses from unknown causes occur annually. It is critically important to improve our ability to identify enteric pathogens and to characterize risk factors associated with potentially distinct diarrheal illnesses. Objectives: Risk factors for hospital admission among patients with diarrhea are not well characterized. In this study, we analyzed risk factors for hospitalization among outpatients with complaints of diarrhea, focusing on patients with multiple enteric pathogens. Additionally, we investigated the most commonly recognized infectious cause of diarrhea among hospitalized individuals, Clostridium difficile, in order to better understand its increasing frequency in community-onset diarrhea. Methods: Through the use of core epidemiologic methodology in combination with state-of-the-art laboratory techniques, known and putative pathogens were identified in patients with diarrhea presenting to selected emergency departments and ambulatory care clinics in Baltimore, Maryland, and New Haven, Connecticut from 2002-2007. Results: Of 1197 outpatients with diarrhea, 405 (35.0%) had definitive enteric pathogens, 527 (45.8%) had definitive or possible pathogens, 62 (5.4%) had multiple definitive pathogens, and 142 (12.3%) had multiple definitive or possible pathogens. At presentation, 233 patients (19.5%) were admitted to the hospital and 919 (76.8%) were not. When forced into a multivariable logistic regression model, multiple enteric pathogens (odds ratio (OR)=0.86, 95% confidence interval (CI)=0.61-1.21) lacked significance; however, age >65 (OR=7.2, 95% CI=4.16-12.46), history of prior gastrointestinal (OR=3.65, 95% CI=2.12-6.29) or immunocompromising co-morbid conditions (OR=2.67, 95% CI=1.69-4.21), hospitalization in the previous month (OR=3.24, 95% CI=2.07-5.07), and presentation at an emergency department (OR=2.53, 95% CI=1.72-3.73) were significantly associated with hospitalization. Of 1,091 outpatients tested for C. difficile toxin, 43 (3.9%) had positive results. Seven had no recognized risk factors, and three of these had neither risk factors nor co-infection with another enteric pathogen. Conclusions: A significant portion of outpatients with diarrhea were hospitalized. Identification of enteric pathogens or multiple pathogens was not associated with increased likelihood for hospitalization after adjustment for age and past medical conditions. Additionally, most outpatients with C. difficile infection had either recognized risk factors or co-infection.