There is increasing evidence that hepatitis B virus (HBV) infection of an immunosuppressed host is associated with the appearance of virus mutants. To characterize the virus circulating in patients in detail, eleven full-length HBV genomes, isolated from the serum of five highly viraemic renal transplant recipients with liver disease, were cloned and sequenced. The genomes contained deletions in the C gene, deletions in the pre-S1/2 region frequently removing the pre-S2 initiation codon, premature termination codons in the pre-S1 or S region, and/or deletions/insertions in the X gene/core promoter. The mutations occurred at different positions and in various combinations; even mutant genomes circulating within a patient differed strikingly. It is concluded that long-term immunosuppression is associated with the occurrence of heterogeneous populations of partially defective HBV characterized by a specific mutation pattern. Efficient intracellular trans-complementation probably enables high virus replication in vivo.