Many-body searches in molecular replacement are usually carried out sequentially and each step benefits from the structural information obtained in previous rotational and translational stages. In this context, the incorporation of known structural information has proved to enhance the discrimination of a rotation function in Patterson space when many independent molecules have to be located in the asymmetric unit of the crystal cell. This improvement is achieved by subtraction of the contributions of already positioned molecules from the observed Patterson map, which makes the determination of the correct orientation of the remaining molecules easier. The quality of the resultant difference Patterson map is greatly influenced by the application of a bulk-solvent correction to the structure-factor amplitudes of the molecules that are being subtracted. The results obtained in the rotation search benefit both from the availability of high-resolution data and from the combination of the subtraction strategy and the refinement of a great number of the peaks of the rotation function.