Phytohemagglutinin (PHA)- and antigen-induced DNA synthesis was measured in leukocyte cultures from 16 patients with lepromatous leprosy, 12 with tuberculoid leprosy, and 20 normal persons. In cultures containing 20% autologous plasma, the responses of lepromatous leukocytes to PHA, purified protein derivative (PPD), streptolysin O (SLO) and antigens of Mycobacterium leprae were significantly below those of the control group. Simultaneous culture of lepromatous leukocytes washed and suspended in normal homologous plasma (20%) resulted in significantly increased SLO-induced DNA synthesis and a modest increase in response to PPD. The response to PHA and antigens of M. leprae remained unchanged. Except for PPD, the responses of tuberculoid leukocytes in autologous or homologous plasma were not significantly lower than normal. Nine of 14 lepromatous plasmas were found to contain a factor that depressed the response of normal leukocytes to PPD and SLO but not to PHA. The depressor factor is non-dialyzable, stable after prolonged storage at -20°C, and resistant to heating at 56°C; its activity is lost at relatively low dilutions. It is concluded that the in vitro demonstration of impaired cellular immune function in patients with leprosy may reflect a primary cellular defect, the depressive effect of a humoral factor, or both, to varying degrees.