Longitudinal data examining travel-associated illness patterns are lacking. To address this need and determine trends and clusters in travel-related illness, we examined data for 2000-2010, prospectively collected for 42,223 ill travelers by 18 GeoSentinel sites. The most common destinations from which ill travelers returned were sub-Saharan Africa (26%), Southeast Asia (17%), south-central Asia (15%), and South America (10%). The proportion who traveled for tourism decreased significantly, and the proportion who traveled to visit friends and relatives increased. Among travelers returning from malaria-endemic regions, the proportionate morbidity (PM) for malaria decreased; in contrast, the PM trends for enteric fever and dengue (excluding a 2002 peak) increased. Case clustering was detected for malaria (Africa 2000, 2007), dengue (Thailand 2002, India 2003), and enteric fever (Nepal 2009). This multisite longitudinal analysis highlights the utility of sentinel surveillance of travelers for contributing information on disease activity trends and an evidence base for travel medicine recommendations.