Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpes virus found in all forms of Kaposi's sarcoma (KS) including KS among immunosuppressed transplant patients. It is unknown whether this virus is transmitted by organ transplantation or is reactivated during immunosuppression among those patients infected before transplantation. To investigate the risk of KSHV transmission during organ transplantation, we conducted a case-control study of transplant recipients with and without KS matched to their respective donors. Sera were collected at time of transplantation and tested in a randomized and blinded fashion using four KSHV serologic assays testing for antibodies to both latent and lytic phase antigens. Ten (91%) of 11 organ recipients who developed KS were seropositive prior to transplantation by one or more of the assays compared with two (12%) of 17 control organ recipients (OR = 75, 95% CI = 4.7, 3500). KS cases were more likely to have been born in southern Italy where KS is endemic than the recipient controls or either donor group. Only four (36%) of 11 donors to case patients and three (18%) of 17 donors to control patients were seropositive (P = .38, two-tailed Fisher's exact test). KSHV transmission could not be ruled out for the single KS patient seronegative at transplantation and clear evidence for organ-related transmission was found for another KS patient outside of the case-control study. Antibodies to KSHV are detectable in the sera from most transplant recipients before initiation of immunosuppressive treatment suggesting that KS among immunosuppressed transplant patients is primarily due to virus reactivation. KSHV transmission, however, from an infected allograft can occur, and our study reports the first documented case of person-to-person transmission of KSHV.