The immortalization of human B-lymphoblastoid cell lines (LCL) transformed by Epstein-Barr virus (EBV) is accompanied by two major events: increase in telomerase activity and change in karyotype from normal diploid to aneuploidy. We investigated the effect of genetic factors on the incidence of immortalization by putting old and new data together to collect enough samples for statistical analysis. Among 50 LCL from normal individuals, 5 LCL (10.0%) were immortalized and the remaining 45 LCL were mortal. None of the 44 LCL (0%; P < 0.031 against normal individuals by chi square test) from patients having Werner syndrome (WS), a recessive genetic disorder showing premature aging, were immortalized. Among 11 LCL from a family with a tendency to have hereditary type 2 diabetes mellitus, 5 LCL (45.5%; P < 0.0040 against normal individuals, P < 0.00001 against WS patients) were immortalized. Duplicated measurements of the lifespan of 33 LCL showed a good coincidence (r=0.785) between the first and second estimations, indicating that each mortal LCL has a predetermined lifespan. These results strongly suggest that the normal WRN gene, the causative gene of WS, is essential for LCL to immortalize, and genetic factor(s) of a family having diabetes mellitus increases immortalization, implicating that host genetic factors affect immortalization of EBV and probably carcinogenesis by EBV.