In a previous report we provided evidence that the three major hypoxanthine-guanine phosphoribosyltransferase (HGPRT; EC 220.127.116.11) isozymes in human erythroid cells are derived by posttranslational modification of a single enzyme [Johnson, G. G. et al. (1982). Biochemistry 21: 960]. In the experiments reported here we provide further evidence that the modified isozymes have a catalytic activity that is at least as great as that of the unmodified enzyme. However, we also show that the total HGPRT activity decrease with red-cell age, by a factor of approximately 4, and that this decrease in activity is paralleled by a loss in HGPRT immunoreactive protein. We estimate that the loss of HGPRT activity and immunoreactive protein as well as the changes in the relative abundances of the major isozymes occur early in the cell's life.