There is little information available concerning the possible effects of ascorbic acid on glucose-6-phosphate dehydrogenase (G-6-PD) - deficient erythrocytes. We therefore studied the survival of G-6-PD- deficient cells, incubated with ascorbic acid, in rats with partial reticuloendothelial and complement blockade. Animals were pretreated with ethyl palmitate and cobra venom factor. They were then transfused with 51Cr-labeled erythrocytes which had been incubated in the presence or absence of ascorbic acid. G-6-PD-deficient cells, incubated with ascorbic acid, had impaired survival when compared to that of controls. G-6-PD-deficient cells, in the absence of ascorbic acid, had survival times equal to those of normal control erythrocytes. At the concentrations used, ascorbic acid did not appear to alter the survival of normal cells. Ascorbic acid causes premature loss of G-6-PD- deficient human erythrocytes in this rat model. On the basis of previous clinical and experimental observations, as well as this study, caution should be used when administering ascorbic acid in large doses to individuals who might be G-6-PD deficient.