Acute hemolytic anemia associated with red blood cell (RBC) glucose-6-phosphate dehydrogenase (G6PD) deficiency is commonly encountered in the Mediterranean basin. Nevertheless, concomitant clinical evidence of white blood cell G6PD deficiency is extremely rare in Israel. This study sought to assess simultaneously levels of G6PD activity in polymorphonuclear leukocytes (PMN) and in red blood cells (RBC) of patients with G6PD deficiency, including full-term newborn infants. In PMN, the correlation between G6PD activity, hexose monophosphate shunt activity, and superoxide anion release was evaluated. In G6PD-deficient patients, a parallel and significantly decreased G6PD activity was found in neutrophils (range of activity 0 -4.5 IU/10 6 PMN) and erythrocytes (range of activity 0 -1.8 IU/g Hb), compared with healthy controls (5-23 IU/10 6 PMN and 2.4 -6.4 IU/g Hb, respectively). A positive correlation was found in PMN between the levels of G6PD activity, hexose monophosphate (HMP) shunt activity, and superoxide anion release (p Ͻ 0.01). Nevertheless, all patients' bactericidal activity of neutrophils remained in the range of healthy controls. Although many episodes of acute hemolytic anemia were recorded, no increased incidence of pyogenic infections was observed in any group of patients investigated. Neutrophil and erythrocyte G6PD levels were re-assessed in some of these patients several times a day. A significant diurnal fluctuation of the enzyme activity was found. It is speculated that the patients produce fluctuating daily quantities of NADPH, sufficient to initiate the neutrophil respiratory burst and to achieve normal bactericidal activity, necessary to prevent the development of microbial infections. (Pediatr Res 55: 807-813, 2004) Abbreviations G6PD, glucose-6-phosphate dehydrogenase CGD, chronic granulomatous disease HMP, hexose monophosphate RBC, red blood cell WBC, white blood cell PMN, polymorphonuclear Erythrocyte G6PD deficiency, mainly manifested by hemolytic anemia induced by oxidative stress to the RBC, is a relatively common worldwide disorder (1). The G6PD gene is located on the X chromosome, leading to the clinical manifestations of the disease being usually confined to hemizygous men, although female carriers with marked expression of the aberrant allele may also suffer (2). This entity is encountered among various ethnic groups in Israel as well (3-5).G6PD catalyzes the reduction of NADP to NADPH, the first step of the HMP pathway. Phagocytic leukocytes use NADPH as a substrate for the NADPH-oxidase enzyme, which contributes to the killing of ingested microorganisms by subjecting them to highly toxic reactive oxygen species (ROS) and bringing about myeloperoxidase-catalyzed halogenation of proteins. Recently, it was reported that the killing activity of neutrophils is enhanced in yet another way by the NADPH oxidase (6).