Background. No systematic studies exist on sex and gender differences across a broad range of travel-associated diseases. Methods. Travel and tropical medicine GeoSentinel clinics worldwide contributed prospective, standardized data on 58, 908 patients with travel-associated illness to a central database from 1 March 1997 through 31 October 2007. We evaluated sex and gender differences in health outcomes and in demographic characteristics. Statistical significance for crude analysis of dichotomous variables was determined using x 2 tests with calculation of odds ratios (ORs) and 95% confidence intervals (CIs). The main outcome measure was proportionate morbidity of specific diagnoses in men and women. The analyses were adjusted for age, travel duration, pretravel encounter, reason for travel, and geographical region visited. Results. We found statistically significant (P < .001 ) differences in morbidity by sex. Women are proportionately more likely than men to present with acute diarrhea (OR, 1.13; 95% CI, 1.09-1.38), chronic diarrhea (OR, 1.28; 95% CI, 1.19-1.37), irritable bowel syndrome (OR, 1.39; 95% CI, 1.24-1.57), upper respiratory tract infection (OR, 1.23; 95% CI, 1.14-1.33); urinary tract infection (OR, 4.01; 95% CI, 3.34-4.71), psychological stressors (OR, 1.3; 95% CI, 1.14-1.48), oral and dental conditions, or adverse reactions to medication. Women are proportionately less likely to have febrile illnesses (OR, 0.15; 95% CI, 0.10-0.21); vector-borne diseases, such as malaria (OR, 0.46; 95% CI, 0.41-0.51), leishmaniasis, or rickettsioses (OR, 0.57; 95% CI, 0.43-0.74); sexually transmitted infections (OR, 0.68; 95% CI 0.58-0.81); viral hepatitis (OR, 0.34; 95% CI, 0.21-0.54); or noninfectious problems, including cardiovascular disease, acute mountain sickness, and frostbite. Women are statistically significantly more likely to obtain pretravel advice (OR, 1.28; 95% CI, 1.23-1.32), and ill female travelers are less likely than ill male travelers to be hospitalized (OR, 0.45; 95% CI, 0.42-0.49). Conclusions. Men and women present with different profiles of travel-related morbidity. Preventive travel medicine and future travel medicine research need to address gender-specific intervention strategies and differential susceptibility to disease. © 2010 by the Infectious Diseeses Society of America. All rights reserved.