In order to investigate the upper limits of safety to primaquine, the effect of weekly standard doses of 45 mg of primaquine and 300 mg of chloroquine on G6PD deficient Caucasians was studied. Seven sensitive Caucasians had significant hemolysis after a single weekly dose of the drugs measured by the change in the 51Cr tagged red cell survival and in the hematocrit levels. G6PD deficient 51Cr tagged red cells belonging to some of these subjects transfused into normals, receiving thereafter weekly doses of primaquine, were rapidly destroyed. Three G6PD deficient Sardinians did not show any hemolysis after ingestion of weekly doses of primaquine. Their red cells, however, transfused into normals, who received weekly standard doses of primaquine, were also rapidly destroyed. Investigations should establish if environmental factors faulty absorption of primaquine, different metabolic breakdown of the drug or metabolic differences in the G6PD deficient red cells are responsible for this peculiar behavior. As far as the protective role of SH donor drugs is concerned, preliminary clinical studies have failed to show any significant protective action of these drugs. The apparent in vitro protection obtained by preincubating normal intact red cells with cysteine or cysteamine prior to the exposure of the cells to NEM, could possibly be ascribed to chemical reactions between the two compounds.