Objectives: To evaluate the mortality experience of 11,318 employees of a large, US-based international airline who worked as a flight attendant for 1 or more years. Based on previous studies, the primary a priori outcomes of interest were breast cancer and melanoma. Methods: Vital status was updated through 2002, and life table analyses were conducted. Cumulative exposure to cosmic radiation was estimated from work history data and cosmic radiation estimates derived from flight schedules published in the Official Airline Guide. Results: Overall, mortality from all causes (796 deaths, standardised mortality ratio (SMR) 0.81, 95% CI 0.75 to 0.87) and all cancers (SMR 0.77, 95% CI 0.67 to 0.87) was less than expected based on US mortality rates. However, mortality from all causes among men (SMR 1.16, 95% CI 1.05 to 1.27) was elevated, primarily due to an elevation in mortality from HIV-related diseases (SMR 16.68, 95% CI 13.67 to 20.16). Mortality was also elevated for non-Hodgkin’s disease (SMR 2.52, 95% CI 1.15 to 4.78) among men; for alcoholism (SMR 3.08, 95% CI 1.47 to 5.66), drowning (SMR 5.64, 95% CI 2.06 to 12.27) and suicide (SMR 1.44, 95% CI 0.96 to 2.08) among women; and for railway, water and air transportation accidents (SMR 3.40, 95% CI 1.47 to 6.71). Mortality from non-melanoma skin cancer (SMR 6.29, 95% CI 1.30 to 18.40) was elevated among men based on three deaths; no deaths from non-melanoma skin cancer were observed among women. Mortality from breast cancer among women (SMR 1.05, 95% CI 0.80 to 1.35) and from melanoma (seven deaths, SMR 1.15, 95% CI 0.46 to 2.37) was not significantly elevated. Mortality from breast cancer was not related to duration of employment or estimated cumulative exposure to cosmic radiation. Conclusion: We found no evidence that flight attendants are at increased risk of mortality from breast cancer or melanoma. Limitations include reliance on mortality data and limited power to detect an excess for rare cancers such as melanoma.