The ability of peripheral blood lymphocytes to respond to phytohemagglutinin (PHA) in vitro was studied in patients with Down's syndrome. The response was measured by the increase in DNA polymerase activity and the rate of incorporation of tritiated thymidine by the cultured lymphocytes. These activities were significantly lower in PHA-stimulated lymphocytes from patients with Down's syndrome compared with age- and sex-matched, mentally retarded patients without Down's syndrome from the same institution and the normal healthy volunteers. The impairment in response to PHA does not seem to be related to the presence of Australia antigen in patients with Down's syndrome or to institutionalization itself. In contrast to DNA polymerase activity and thymidine-(3)H uptake, there was no significant difference in the percentage of blast transformation in the three groups studied. The poor response of the lymphocytes from patients with Down's syndrome to a mitogenic stimulus could reflect an impairment of cellular immune functions in these patients which may be one of the factors contributing to the vulnerability of these patients to repeated or persistent infections.