The Blood Donor Competency, Autonomy, and Relatedness Enhancement (Blood Donor CARE) project was designed as a practical application of self-determination theory to encourage retention of first-time donors. Self-determination theory proposes that people are more likely to persist with behaviors that are internally-motivated, and that externally-motivated behavior can evolve and become internalized given the appropriate socio-environmental conditions. According to self-determination theory, motivation to engage in blood donation may become increasingly self-determined if the behavior satisfies fundamental human needs for competence (a sense of self-efficacy to achieve specific goals), autonomy (a sense of volitional control over one’s behavior), and relatedness (a sense of connection to a larger group). The primary aim of this randomized controlled trial is to examine the effect of competence, autonomy, and/or relatedness interventions on donor retention. Using a full factorial design, first-time donors will be assigned to a control condition or one of seven intervention conditions. Donation competence, autonomy, and relatedness, along with additional constructs associated with return donation, will be assessed before and after the intervention using online surveys, and donation attempts will be tracked for one-year using blood center donor databases. We hypothesize that, compared to the control condition, the interventions will increase the likelihood of a subsequent donation attempt. We will also examine intervention-specific increases in competence, autonomy, and relatedness as potential mediators of enhanced donor retention. By promoting first-time donor competence, autonomy, and relatedness our goal is to enhance internal motivation for giving and in so doing increase the likelihood of future donation.