In the USA, erythrocytic glutathione reductase (GSSG-R) deficiency is significantly more common, and can be considerably more pronounced in hospitalized patients (118/3198) than in outpatients (37/1639) or in apparently healthy persons (12/849). Retrospective analysis of illnesses found in 118 inpatients with erythrocytic GSSG-R deficiency revealed a striking and previously unsuspected association of the enzyme deficiency with a variety of chemotherapeutically treated hematological or nonhematological malignancies (51/118 patients, 43.2%, or 51/170 diagnoses, 30.0%). The prevalence of erythrocytic GSSG-R deficiency also increased in malnutrition, liver disease, and sepsis. Drugs of the nitrosourea class, particularly BCNU [1, 3-bis(2-chloroethyl)-1-nitrosourea] are causally implicated in the association of GSSG-R deficiency with malignancies. Severe of complete GSSG-R deficiency may handicap host response to infections.