Background Traveling the world may result in infection with tropical or other travel‐associated diseases. This applies increasingly also to people with immune‐compromising and other medical conditions, as well as to elderly individuals. To reduce exposure and susceptibility to health risks, there is a need for appropriate pre‐travel advice for these particular groups of travelers. Methods In this observational study, we analyzed the overall risk of health problems among travelers with underlying medical conditions who attended the University of Amsterdam's Academic Medical Center's (AMC) travel clinic from January to October 2010. Telephone questionnaires were administered to 345 travelers with underlying conditions and 100 healthy travelers. Results The most common underlying medical conditions studied included: (1) diabetes mellitus; (2) impaired immunity due to use of immune‐suppressing medication; (3) reduced gastric barrier; and (4) HIV infection. The overall incidence of travel‐related diseases (TRDs) was higher among those patients with underlying medical conditions compared to healthy travelers incidence rate ratio (IRR) 2.26, 95% CI (1.29–3.98). Of all diseases reported, gastrointestinal disease, fever, and respiratory problems were reported most frequently. Travel to Central America, South Central Asia, Northeast Asia, and North Africa was associated with increased risk of contracting TRD. Hepatitis B protection was absent or unknown in 75% of these travelers. Conclusions Travelers with medical conditions had a higher risk of obtaining TRD, predominantly gastrointestinal in nature.