Donation eligibility is based on hemoglobin (Hb) level among other factors. This study assesses factors that influence Hb levels among first-time (FT) donors returning for a second donation. Allogeneic FT donors who successfully donated a red blood cell (RBC)-containing donation on their index presentation and returned to donate at least once more between August 1, 2009, and July 31, 2012, were included. Interdonation intervals and delta Hb (subsequent donation - index donation value) were calculated. Multivariable logistic regression and survival analysis methods were used to determine factors associated with 1) Hb recovery to preindex donation value or 2) deferral at the second presentation. During the study, 135,040 FT donors returned to donate. Overall, 44% of donors returned with a Hb level at or above their index value (defined as recovery for this study), 48.1% for males and 39.9% for females. Logistic regression revealed that the factor most strongly associated with Hb recovery was index Hb, with lower Hb having much higher odds of recovery. Shorter interdonation intervals were associated with decreased likelihood of recovery. Certain demographic characteristics were also associated with higher odds of recovery. Factors associated with deferral were similar to the factors associated with recovery, except for donor sex. As early as the second blood donation, allogeneic donors can be differentiated into two subpopulations: those who recover to index Hb levels and those who do not. Current data routinely collected by US blood centers cannot reliably distinguish between the two groups.