The X-ray structure of a decameric form of a complex of human cyclophilin A (CypA) with the immunosuppressive drug cyclosporin A (CsA) has been determined. The crystals of space group P43212 with cell dimensions a = b = 95.2 A, c = 280.0 A have five copies of the cyclophilin A/cyclosporin A complex in the asymmetric unit. The structure was solved by molecular replacement techniques, using a known cyclophilin A model. Procedures were developed to construct a self-rotation function using the results of cross-rotation searches. The comparison of experimental and constructed self-rotation maps was an important aid in selecting the correct rotation function solution. The translation functions revealed the presence of a cyclic pentamer. A crystallographic dimer axis passes through the non-crystallographic 5-fold rotation axis of the pentameric asymmetric unit, and generates a decameric "sandwich" of CypA/CsA heterodimers that has 52 symmetry. The five CypA/CsA protomers were refined independently using all data to 2.8 A giving a final crystallographic R-factor of 15.7%. Despite the constraints due to the packing arrangement within the decamer, the CypA and CsA conformations are similar to other CypA/CsA structures determined by X-ray crystallography and NMR spectroscopy. The hydrophobic CsA molecules are embedded in the middle of the decameric sandwich with only 20% of their surface exposed to solvent. The binding loop of CsA (residues 1 to 3 and 9 to 11) comprising 42% of the CsA surface, is buried in the peptidyl-prolyl-cis-trans isomerase active site of the cognate binding partner CypA, while the effector loop (residues 4 to 8) packs in the core of the decamer making hydrogen-bonding and van der Waals contacts with three neighbouring molecules. The environment of CsA in the decamer has been analysed and may provide a mimic for the interactions likely to occur between the CypA/CsA complex and its biological target calcineurin. There is no evidence to suggest that the decameric sandwich itself plays a role in immunosuppression by inhibiting calcineurin. However, the chaperone/foldase activity of CypA could require oligomer formation for its biological function.