One of the major barriers to successful transplantation of immediately vascularized organs between discordant species is the presence of natural antibodies (NA) in the recipient. While natural antibodies can be depleted by plasmapheresis and/or organ absorption, they rapidly return to the circulation after such procedures. It will be desirable to suppress NA for longer periods of time. Since NA appear to be produced at least in part by CD5+ B cells, it was important to evaluate whether mycophenolate mofetil (RS-61443), a novel immunosuppressant that has been shown to suppress normally elicited antibody synthesis, would also be able to suppress NA. Adult rats were splenectomized, and 2 days later, 9 plasma exchanges, each of 4 ml, were performed. One group of rats received RS-61443 at 40 mg/kg/day (the dose described as efficacious for suppressing elicited antibodies in rats) starting immediately after the last exchange for 7 days, and then 20 mg/kg/day for an additional 7 days; no drug was given to the control group. NA levels were measured at various times by ELISA, using guinea pig platelets extracts as the target. Splenectomy alone led to a significant decrease from the control levels of NA; liters were further reduced by the plasma exchanges. In the absence of RS-61443, NA titers rose steadily, starting at 24 hr after the last plasma exchange. In contrast, administration of RS-61443 resulted in levels of NA on day 7 not significantly different from those after plasma exchange, reducing the dose of RS-61443 to the 20 mg/kg/day level during week 2 allowed the gradual return of NA. Administration of RS-61443 at the 40 mg/kg/day dose to rats after splenectomy alone led to a clear and significant further decrease in NA levels over the first week. It has been shown that RS-61443 can be administered for longer periods. The data presented suggest that use of this drug, perhaps with more conventional agents, may allow suppression of NA for a significant period after transplantation.