Measures related to red cell oxygen transport were evaluated in 17 hemodialysis patients receiving androgen therapy, 15 untreated hemodialysis patients and 15 normal subjects. Hemoglobin levels were higher in androgen-treated patients than in the untreated population and were directly related to the reticulocyte index. Hill coefficients were normal, and in vivo P5O values were increased to the same degree in both dialysis groups. However, DPG and serum phosphate explained 70% and 12%, respectively, of the variance in P5O in untreated patients but only 2% and 5% in androgen-treated subjects. In contrast, sample pH explained 34% of the variance in P5O in the androgen-treated group and less than 1% in the untreated dialysis population. Despite the relative importance of pH as a determinant of P5O in patients on androgen therapy, the Bohr coefficient in this group was only about half of that in untreated dialysis subjects. Androgen-treated patients also had lower red cell ATP levels. Finally, the expected correlation of MCHC with pH was noted in untreated dialysis subjects but not in patients receiving androgens. We conclude that androgen therapy in hemodialysis patients in addition to increasing red cell production, directly alters red cell metabolism. Moreover, although the androgen regimens used did not change the net oxygen transport characteristics of hemoglobin, they decreased the responsiveness of hemoglobin-oxygen affinity to changes in pH, DPG and phosphate. Thus, red cell adaptation to changes in oxygen supply and/or demand may be limited in androgen treated patients, and the improvement in clinical performance expected from androgen-stimulated erythropoiesis may not be realized.