Vesicles of a variety of types of phosphatidylcholine have been shown to be suitable donors of phosphatidylcholine to intact rat erythrocytes in the presence of a specific phosphatidylcholine exchange protein. Coincident with the progression of phosphatidylcholine exchange is the onset of hemolysis, occurring at degrees of exchange characteristic for the type of phosphatidylcholine employed. During exchange with the dimyristoyl, dipalmitoyl and distearoyl species, hemolysis starts when 27%, 25% and 22% of the native phosphatidylcholine is replaced by these disaturated species, respectively. In the case of dielaidoylglycerophosphocholine and 1-stearoyl-2-oleoylglycerophosphocholine hemolysis starts after the introduction of 30% and 28%, respectively. In contrast, the replacement of native erythrocyte phosphatidylcholine with egg phosphatidylcholine, and the dioleoyl species up to levels of 60% does not result in rapid hemolysis. Despite such functional consequences, overall contents of the individual phospholipids and cholesterol are normal. Accompanying the biochemical events are morphologic changes, including echinocyte an spherocyte formation. The structure-function implications and possible mechanisms of hemolysis are discussed.