The mechanism by which human monocytes increase the osmotic fragility of red cells sensitized with Rhesus alloantibodies anti-D was studied in vitro. Both the increase in osmotic fragility and the lysis of red cells by monocytes were enhanced by cytochalasin B and were inhibited by hydrocortisone. These effects were similar to the effects of these agents on lysosomal enzyme release by monocytes. However, hydrocortisone was completely ineffective when added I h after mixing monocytes and sensitized red cells. This indicates that the damage responsible for the fragility increase and lysis is completed within I h and suggests that it is due to lysosomal enzymes released by the monocytes. Since for the full expression of the osmotic fragility increase and lysis an incubation time much longer than I h is required, it appears that the latter phenomena are the non-specific sequelae of damage inflicted upon the red cell by released lysosomal enzymes.