Fusion of chromaffin granule ghosts with model phospholipid vesicles is dependent on the composition of the vesicle membrane. Cardiolipin was found to make possible a process of fusion in the absence of calcium. This calcium-independent fusion appears to be partially protein-dependent. Upon interaction with pure cardiolipin vesicles calcium stimulates both fusion of chromaffin granule ghosts and release of catecholamines from intact chromaffin granules. We suggest that the release of catecholamines is not only a consequence of the fusion process. The relevance of protein-lipid interaction and the importance of the formation of HII phases or other non-lamellar phases, on the fusion of chromaffin granules are discussed.