Sera of 63 patients with systemic lupus erythematosus (SLE), 34 with rheumatoid arthritis (RA), 38 with Felty's syndrome (FS), and 13 with other rheumatic diseases were tested for cold-reacting (CRC) and warm-reacting (WRC) cytotoxins against lymphocytes, granulocytes, and monocytes. The incidences of CRC against lymphocytes were in SLE 48%, in RA 38%, and in FS 63%. The respective values for CRC against granulocytes were 8, 24, and 21% and against monocytes 14, 26, and 11%. The respective values of WRC against lymphocytes were 23, 8, and 20%; against granulocytes 18, 38, and 22%; and against monocytes 63, 33, and 40%. Whereas the incidence of CRC against lymphocytes was significantly higher than that of WRC ( P < 0.01), the opposite was noted with regard to monocytes. WRC against granulocytes were observed more often than CRC, but the difference was not significant. Antilymphocyte CRC's were the most potent as estimated by the percentage of killed cells and by the maximal dilution of the sera showing cytotoxic activity. Cytotoxicity at 37°C was almost invariably weaker than at 4°/24°C. Elution of cytotoxins from different cells showed that many but not all eluates killed more than one type of cells. Several eluates from sera containing both cold and warm cytotoxins expressed strong cytotoxic activity at 4°/24°C and a weaker but definite cytotoxic activity at 37°C. In other cases such eluates were cytotoxic only in the cold whereas supernatants retained warm-reacting cytotoxins. Lymphocytotoxins reduced to various degrees E and EAC rosettting capacity of allogeneic and of autologous lymphocytes. No correlation to the percentage of killed cells was observed. Granulocytotoxins reduced phagocytic activity of the surviving polymorphonuclears. We assume that the cytotoxic activity observed is due to immunoglobulins, but this requires further investigation. Therefore, sera of many patients with rheumatic diseases have heterogeneous population of cytotoxins against lymphocytes, granulocytes, and monocytes, reacting at low and/or physiologic temperatures.