Impairment of purine metabolism due to adenosine deaminase (ADA) deficiency is associated with a severe combined immunodeficiency (SCID). Polyethylene glycol‐modified ADA (PEG‐ADA) has provided noncurative, life‐saving treatment for these patients, but full immune recovery is not achieved with this therapy. Since ADA‐SCID is perhaps the most difficult form of SCID to handle clinically, understanding the benefits and limitations of PEG‐ADA therapy may be relevant for treatment selection. To this purpose, we analyzed the rate of thymic output, T and B cell repertoires, number of T cell divisions, IFN‐γ and IL‐4 production, and the extent of cell death in five ADA‐SCID patients following a prolonged period of treatment with PEG‐ADA. We found that thymic output was low in these patients. However, their T cell repertoire was heterogeneous, and their T lymphocytes produced cytokines upon activation and responded to mitogen stimulation, although with different kinetics. Furthermore, a high number of peripheral T lymphocytes were committed to apoptosis. Anomalies were also observed in the B cell compartment, with oligoclonal expansions of B cell clonotypes in two patients. Our data indicate that decreased thymic function, B cell oligoclonality, and increased spontaneous apoptosis may be the mechanisms by which the immunodeficiency of ADA‐SCID patients persists in spite of treatment with PEG‐ADA.