Lymphocytes secreting anti-IgC antibodies, rheumatoid factors (RF), can be detected in the peripheral bloods, synovial fluids, and bone marrows of patients with seropositive rheumatoid arthritis by using a direct plaque-forming cell (PFC) assay with sheep erythrocytes sensitized with reduced and alkylated rabbit IgG hemolysin. The autospecific nature of the RF produced by RF-PFC was indicated by inhibition studies in which the order of patency was human IgG greater than rabbit IgG greater than bovine IgG. In metabolic studies puromycin, cycloheximide, and venblastine suppressed RF-PFC. Cyclic AMP and cyclic GMP were without effect. A need was recognized for using full tissue culture media during the cell separation and plaquing procedures to optimize detection of the RF-PFC. RF-PFC may appear in the blood of patients intermittently despite their continuing presence in the bone marrow. They have been found in the peripheral blood, especially during acutely exacerbating polyarticular synovitis, generalized vasculities, or generally active, aggressive disease. RF-PFC were found in synovial effusions of new or recrduescent acute synovitis. RF-PFC were observed to disappear from the peripheral circulation and the bone marrow during therapy with cytotoxic drugs. The data are consistent with the hypothesis that the appearance of RF-PFC in the peripheral blood represents an anamnestic response to transiently appearing antigen. The nature of the antigen is not specified. The bone marrow may be a site of origin of RF-PFC.