BACKGROUND: Donor and red blood cell (RBC) component factors may affect patient outcomes after RBC transfusions, but data on the magnitude and consequences of these associations are limited. STUDY DESIGN AND METHODS: In this retrospective cohort study, we analyzed associations between 10 donor and component factors-including donor age, hemoglobin, parity, sex, and component storage time-and changes in 55 clinical laboratory markers measured within 24 h before and after RBC transfusions. Primary analyses used data from the Swedish SCANDAT3-S database, with findings replicated in the U.S. REDS-III database. The primary outcome was the transfusion-related change in pre- and post-transfusion values of the laboratory markers, normalized per RBC unit transfused. RESULTS: After adjusting for the false discovery rate, 33 significant associations were identified, with 20 replicated in the SCANDAT replication sample or the REDS-III cohort after Bonferroni corrections, and 18 remaining after visual assessment. Higher donor hemoglobin concentration consistently led to greater increases in recipient hemoglobin and measures of RBC mass. Extended component storage times were associated with elevated recipient bilirubin and carboxyhemoglobin levels. Differences in recipient hemoglobin response between the SCANDAT3-S and REDS-III cohorts suggest potential variations in transfusion efficacy across populations and practices. DISCUSSION: These findings suggest that considering donor hemoglobin and RBC component storage duration could enhance transfusion efficacy, providing avenues for personalized transfusion strategies to improve patient outcomes.