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Introduction: Antibiotic exposure is associated with a long-lasting alteration in gut microbiota, and may be related to subsequent major chronic diseases such as cardiovascular diseases and cancer. No previous prospective cohort study has investigated associations between duration of antibiotic use during adulthood with mortality from major chronic diseases among populations at usual risk.Hypothesis: We investigated whether a longer duration of antibiotic use was associated with elevated risks of all-cause and cause-specific deaths among women.Methods: This study included 37,510 women aged ≥60 y who were initially free of cardiovascular diseases or cancer from the Nurses’ Health Study. The present analysis included women who reported data on antibiotic use on the 2004 questionnaire when the information was first assessed. We calculated hazard ratios (HR) for all-cause mortality, and deaths from cardiovascular disease (ICD-8 [international classification of diseases, eighth revision, ICD-8], codes 390 to 458) and cancer (ICD-8, 140-209) according to total days of antibiotic use per year (none, less than 15 days, 15 days to less than 2 months, or ≥2 months) in late adulthood (age 60 or older). Follow-up time was calculated from the return date of the 2004 questionnaire until the date of death, or end of follow-up (June 30, 2012), whichever occurred first.Results: During 287,474 person-years of follow-up, we documented 2908 deaths from any cause (including 474 cardiovascular deaths and 906 cancer deaths). Longer duration of antibiotic use was significantly associated with higher risk of death from any cause after adjusted for dietary intake, lifestyle factors, hypertension, hypercholesterolemia, diabetes (Ptrend <0.0001), other medication use (such as aspirin, statin, H2 blockers, proton pump inhibitors) (Ptrend =0.001), and other characteristics (Ptrend =0.038). As compared to women who did not use antibiotics, those who used for ≥2 months in late adulthood had significantly increased risks of all-cause mortality (multivariate-adjusted HR 1.27; 95% CI, 1.07, 1.49) and cardiovascular mortality (HR 1.58; 95% CI, 1.02, 2.46), but not cancer mortality (HR=0.86; 95% CI, 0.63, 1.16). The association between long-term antibiotic use in late adulthood and an elevated risk of all-cause death was more evident among women who also used antibiotics in middle adulthood (during age 40-59) (Ptrend=0.002) than among those who did not use during this life stage.Conclusions: Long-term duration of antibiotic exposure especially in late adulthood was associated with increased all-cause and cardiovascular mortality in women.