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Abstract Background and aims The association of blood transfusion with an increase in medium- and short-term mortality in specific populations has been confirmed. However, the correlation between blood transfusion and long-term mortality in the general population remains unclear. This cohort study evaluated the correlation between blood transfusion and overall and cause-specific mortality in the general American adult population. Methods The authors utilized 10 sets of 2-year cycle data (1999-2018) from the National Health and Nutrition Examination Survey on the outcomes of adults who did and did not receive blood transfusions. Propensity score-matching (1:1) was performed based on age, sex, race, education level, marital status, poverty-income ratio, arteriosclerotic cardiovascular disease, cancer, anemia, hypertension, and diabetes status. After controlling for demographic characteristics and clinical risk factors, Cox regression analysis was performed to evaluate the correlation between blood transfusion and all-cause and cause-specific mortality. Results The study included 48,004 adult participants. The risk of all-cause mortality increased by 101 % with blood transfusion, and the risk of cardiovascular mortality increased by 165 %. After propensity score-matching, 6,116 pairs of cases were retained, and the risk of all-cause mortality increased by 84 % with blood transfusion, and the risk of cardiovascular mortality increased by 137 %. The sensitivity analysis results were robust. Conclusions In the general American population, blood transfusion significantly impacts long-term all-cause and cardiovascular mortality and may be an unacknowledged risk factor for death. Thus, the effective management of blood transfusion in the general population may be beneficial. medium shortterm short term confirmed However longterm long unclear causespecific cause 1 2year year 2 19992018 1999 2018 (1999-2018 transfusions scorematching score matching 11 (1:1 age sex race level status povertyincome poverty income ratio disease cancer anemia hypertension factors allcause all 48004 48 004 48,00 participants 16 scorematching, matching, 6116 6 116 6,11 retained 8 13 robust death Thus beneficial 1999201 199 201 (1999-201 (1: 4800 4 00 48,0 611 6,1 199920 19 20 (1999-20 (1 480 0 48, 61 6, 19992 (1999-2 ( (1999- (1999 (199 (19