We investigated the role of thymic function in the immunodeficiency that characterizes bone marrow transplantation (BMT) recipients. The capacity of histocompatible BMT recipients to generate new CD4+ T lymphocytes was determined by FACS analysis with antibodies to the two isoforms of CD45: CD45RA, which is expressed on newly generated CD4 T lymphocytes, and CD45RO, which is expressed on antigen-specific memory CD4 T lymphocytes. Immediately following BMT, all patients had low levels of CD45RA-expressing CD4 T lymphocytes, which increased during the first year and then stabilized. Since thymic function decreases with age in normal individuals, the impact of recipient age on the generation of new CD45RA, CD4 T lymphocytes was determined in BMT recipients with and without chronic graft-vs.-host disease (GVHD). In addition, antigen-specific immune function was determined by assessing in vitro blastogenic response to tetanus toxoid (TT). More than 1 year after transplantation, the results from BMT recipients without chronic GVHD were similar to those of normal individuals; there was an age-dependent decline in the number of CD45RA, CD4 T lymphocytes, and antigen-specific immune function was age-independent. On the other hand, recipients with chronic GVHD had an age-dependent decline in their immune function (r= 0.45 and p= 0.02) that correlated with the number of new CD45RA, CD4 T lymphocytes (p= 0.027) but not the number of memory CD45RO, CD4 T lymphocytes (p= 0.11). Thus recipients with chronic GVHD have decreased antigen-specific immune function that may be due to an acceleration of the normal thymic aging process induced by GVHD and its therapy.