BACKGROUND: Improvement in donor return rates, especially among first-time donors, may significantly improve the blood supply. There are few rigorous studies of the effectiveness of various approaches to donor recruitment, however. STUDY DESIGN AND METHODS: By use of a single-blind, randomized trial design, 6919 post-September 11, 2001, first-time donors were randomly assigned into the following intervention arms: T-shirt incentive versus none, recruitment scripts with a patient story (Script A) versus a complimentary message including the donor's blood type (Script B), and telephone versus e-mail recruitment. Our primary outcome was a second donation within 6 months. Rate ratios (RRs) and 95 percent confidence intervals (95% CIs) were calculated with Taylor series methods. RESULTS: A total of 1421 (20.5%) first-time donors returned within the 6 months, including 1252 with a second and 169 with both second and third donations. The T-shirt incentive was not effective in increasing returns compared to no incentive (20.5% vs. 20.6%; RR, 0.99; 95% CI, 0.91-1.09). Script A was significantly more effective than Script B (22.2% vs. 18.9%; RR, 1.18; 95% CI, 1.07-1.29). E-mail was substantially less effective than telephone recruitment (13.2% vs. 27.8%; RR, 0.48; 95% CI, 0.40-0.57). CONCLUSIONS: A T-shirt incentive had no apparent effect, but an empathetic message significantly improved the return donation rate. E-mail recruitment was substantially less effective than telephone recruitment, perhaps due to technical problems. The study illustrates the utility of the randomized clinical trial study design for testing donor recruitment strategies.