Proliferation of rheumatoid and control peripheral blood mononuclear cells to OKT3, phorbol myristic acid (PMA), phytohemagglutinin (PHA), tuberculin PPD and in the autologous mixed lymphocyte reaction (AMLR) was investigated. Only the responses to PPD and in the AMLR were depressed. This was not due to suppression by OKT8 lymphocytes. The proportion of antigen responsive (T4+ 4B4+) cells was normal but suppressor-inducer (T4+ 2H4+) cells were decreased. The depressed response was not completely restored by addition of recombinant interleukin-2. We propose that a basic defect in rheumatoid arthritis resides in T lymphocytes which react to self-major histocompatibility complex antigens either on their own, as in the AMLR, or as restriction elements in the presentations of soluble antigen.