Immunocompromised travelers to developing countries are thought to have symptomatic infectious diseases more often and longer than non-immunocompromised travelers. Evidence for this is lacking. This study evaluates whether immunocompromised short-term travelers are at increased risk of diseases. A prospective study was performed between October 2003 and May 2010 among adult travelers using immunosuppressive agents (ISA) and travelers with inflammatory bowel disease (IBD), with their non-immunocompromised travel companions serving as matched controls with comparable exposure to infection. Data on symptoms of infectious diseases were recorded by using a structured diary. Among 75 ISA, the incidence of travel-related diarrhea was 0.76 per person-month, and the number of symptomatic days 1.32 per month. For their 75 controls, figures were 0.66 and 1.50, respectively (p > 0.05). Among 71 IBD, the incidence was 1.19, and the number of symptomatic days was 2.48. For their 71 controls, figures were 0.73 and 1.31, respectively (p > 0.05). These differences also existed before travel. ISA had significantly more and longer travel-related signs of skin infection and IBD suffered more and longer from vomiting. As for other symptoms, no significant travel-related differences were found. Only 21% of immunocompromised travelers suffering from diarrhea used their stand-by antibiotics. ISA and IBD did not have symptomatic infectious diseases more often or longer than non-immunocompromised travelers, except for signs of travel-related skin infection among ISA. Routine prescription of stand-by antibiotics for these immunocompromised travelers to areas with good health facilities is probably not more useful than for healthy travelers.