More than 66,000 blood donors are deferred annually in the United States due to travel to malaria-endemic areas of Mexico. Mexico accounts for the largest share of malaria travel deferrals, yet it has extremely low risk for malaria transmission throughout most of its national territory, suggesting a suboptimal balance between blood safety and availability. This study sought to determine whether donor deferral requirements might be relaxed for parts of Mexico without compromising blood safety. Travel destination was recorded from a representative sample of presenting blood donors deferred for malaria travel from six blood centers during 2006. We imputed to these donors reporting Mexican travel a risk for acquiring malaria equivalent to Mexican residents in the destination location, adjusted for length of stay. We extrapolated these results to the overall US blood donor population. Risk for malaria in Mexico varies significantly across endemic areas and is greatest in areas infrequently visited by study donors. More than 70% of blood donor deferrals were triggered by travel to the state of Quintana Roo on the Yucatán Peninsula, an area of very low malaria transmission. Eliminating the travel deferral requirement for all areas except the state of Oaxaca might result in the recovery of almost 65,000 blood donors annually at risk of approximately one contaminated unit collected every 20 years. Deferral requirements should be relaxed for presenting donors who traveled to areas within Mexico that confer exceptionally small risks for malaria, such as Quintana Roo.