OBJECTIVE: To examine the cross-cultural differences of health-related quality of life among people with various health conditions across four countries. METHODS: Analyses were based on 12-page questionnaires mailed to adults in 2000. A total of 38,677 responses were received from France, Germany, Great Britain, and the U.S. Results were subsequently weighted and projected to the national populations of these four countries. Weighting was based on gender, age, and region for the European countries and gender, age, race, and region for the U.S. Participants reported whether they were diagnosed with the following: arthritis, asthma, depression, diabetes, GERD, high blood pressure, high cholesterol, migraines, nasal allergies, or osteoporosis. Physical and mental health status were defined by summary measures of the SF-12 scale. RESULTS: The French reported lower mental health status but better physical health status than people in Germany, Great Britain, and the U.S., regardless of diagnosed health conditions. The opposite was found among arthritis, asthma, and GERD sufferers in Germany, who reported the best mental health status but the lowest physical health. Respondents from Great Britain and the U.S. generally reported SF-12 scores that fell between those of France and Germany, with three notable exceptions. Among people diagnosed with depression, those in the U.S. reported better mental health status. Among people diagnosed with high blood pressure or high cholesterol, those in Great Britain reported the lowest physical health status. CONCLUSION: Self-reported quality of life varied by country regardless of condition. Researchers should consider cross-cultural variations in self-reported quality of life measures when conducting multinational trials. Collapsing data could obscure effects.