Individuals with unstable hemoglobins may become more anemic during episodes of intercurrent viral or bacterial infections. Pathophysiologic mechanisms that are responsible for this phenomenon have not been elucidated. Recently we observed a patient with Hb Zürich [His E7(63)beta leads to Arg] whose anemia worsened during a febrile episode characterized by temperatures ranging between 40 degrees and 41 degrees C, splenomegaly, and the appearance of Heinz bodies in the circulating erythrocytes. There was no history of self-medication and no drugs were administered during hospitalization. To determine the effect of a 3 degrees to 4 degrees temperature elevation above the physiologic range on the rate and degree of Heinz body formation, normal (Hb A) and Hb Zürich bloods were incubated in vitro at 4 degrees C, 37 degrees C, and 41 degrees C for 3, 6, 12, and 24 hours and stained for two minutes at the end of each incubation period with rhodanile blue. No Heinz bodies appeared at 4 degrees C. The rate of Heinz body formation was significantly greater in Hb Zürich than normal blood, both at 37 degrees C and 41 degrees C. These observations suggest that in vivo exposure of red cells to temperatures in the biologic range of fever may contribute to the worsening of anemia that occurs during infections in individuals with unstable hemoglobins. Incubating whole blood at 41 degrees C for three hours and staining with rhodanile blue for two minutes appears to be a simple and effective screening test for Hb Zürich and possibly the other unstable hemoglobins. Also the technique is semi-quantitative and may be useful as a research tool for defining factors altering the in vivo stability of the unstable hemoglobins.