This study assessed the ability of Dorset sheep erythrocytes, a model with a G‐6‐PD deficiency, to predict potential hemolytic responses of human G‐6‐PD deficient erythrocytes to five pharmaceutical agents (i.e. alpha‐naphthol, menadione, primaguine, phenacetin, and quinidine HCl). The sheep erythrocyte responses showed a high concordance with the human responses. The only lack of predictive accuracy was a false negative prediction for the bioactivated metabolites of phenacetin which were positive in the human metabolization system. When these results are combined with earlier published findings with seven additional drugs with a collective total of 22 direct intermodel comparisons, the sheep accurately predicted 11 of 11 non‐hemolytic responses in the human system and 8 of 11 potential hemolytic responses. These results suggest that the sheep model has considerable predictive utility with a tendency toward false negatives but not false positive predictions.