Heterotopic cardiac transplantation was performed in rabbits. The calcium uptake and ATPase activities of microsomal fraction were studied in three groups (group I, normal controls; group II, early transplants; group III, late transplants) during severe rejection as characterized histologically and electrocardiographically. Group III showed a significant decrease in calcium uptake but no difference in ATPase activity compared with groups I or II. The results demonstrate that in the rejecting transplanted hearts there is an uncoupling of microsomal calcium uptake from this ATP splitting function.