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Background: There is a bidirectional effect between sleep disorders and Mediterranean diet (MED), but the joint effect of MED and sleep disorders on mortality is unclear. The aim of this study was to investigate whether there is a synergistic effect of adherence to MED and sleep disorders on all-cause and cause-specific mortality. Methods: The study included 23,212 individuals in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2014. A 9-point evaluation score, alternative Mediterranean diet (aMED) index was used to assess adherence to MED. Sleep disorder and hours of sleep were assessed by structured questionnaires. Cox regression models were used to assess the relationship between sleep disorders, aMED and all-cause mortality, cause-specific mortality (cardiovascular-related death, cancer-related death). The interaction effect of sleep disorders with aMED on mortality was further assessed. Results: Results showed that participants with lower aMED and presence of sleep disorders had significantly higher risk of all-cause mortality and cardiovascular-related mortality (HR, 2.16, 95% CI, 1.49–3.13, P < 0.0001; HR, 2.68, 95% CI, 1.58–4.54, P = 0.0003). A significant interaction effect was found between aMED and sleep disorders on cardiovascular mortality (p for interaction = 0.033). No significant interaction existed between aMED and sleep disorders on all-cause mortality (p for interaction = 0.184) and cancer-related mortality (p for interaction = 0.955). Conclusions: Poorer adherence to MED and sleep disorders synergistically increased long-term all-cause mortality and cardiovascular mortality in NHANES population. [ABSTRACT FROM AUTHOR]