Hepatitis B virus mutants with in-frame deletions in the central part of the core gene are associated with a severe course of infection in long-term immunosuppressed renal transplant recipients. In this study, yeast two-hybrid system was employed to investigate interaction capabilities of two core mutants with deleted 77-93 and 86-93 amino acids. The same mutant and wild-type (WT) protein pairs which form core-like particles inside bacterial cells were able to interact also in two-hybrid system. To find host proteins possibly involved in enhanced pathogenesis of the mutant variants, a human hepatocyte cDNA library was screened for proteins interacting with the mutant but not with the WT core protein. A human protein of unknown function FLJ20850 interacted specifically with the mutant proteins. An attempt to determine interacting regions revealed that FLJ20850 was unable to interact without significant parts of its C- or N-end, and introduced deletion in the central region conferred interaction capability to the WT core protein.