We evaluated a rapid RBC zinc protoporphyrin (ZP) test in 1,147 male and 615 female blood donors to study its value in screening for evolving iron deficiency anemia. Fifteen men (1.8%) and 32 women (7.9%) who returned to donate were found to be anemic. A matched sample analysis between anemic and nonanemic donors demonstrated significant differences in serum ferritin levels, percent iron saturation, and the RBC ZP level from samples collected during the initial evaluation. Red cell ZP correlated well with the natural logarithm of serum ferritin in both men and women who later became anemic. The predictive value of RBC ZP levels compared favorably with that of the serum ferritin level. We also observed a strong association between the yearly donation frequency and RBC ZP concentration. These findings indicate that predonation RBC ZP testing may be useful in screening for iron depletion and potential risk of anemia in blood donors.