In a previous study, we performed serial BK virus (BKV), polymerase chain reaction (PCR) and detected active BKV infection in 70 (35.4%) of 198 renal transplant recipients. In the current study, pre-transplant donor and recipient samples were analyzed for BKV antibody titer and HLA alleles. Donor antibody titer was inversely proportional to onset of viruria, p<0.001, directly proportional to duration of viruria, p=0.014 and directly proportional to peak urine viral titer p=0.005. Recipient pairs receiving kidneys from the same donor were concordant for BKV infection, p=0.017, and had matched sequences of segments of the NCCR and VP1 genes that tended to vary among recipients of kidneys from different donors. We did not see an association of HLA A, B, or DR, HLA allele mismatches or total HLA mismatches and BK infection. However, all 11 recipients with sustained BK viremia received kidneys from donors lacking HLA C7, and 10 recipients also lacked C7. These findings derive from the largest and most comprehensive prospective study of BKV infection in renal transplant recipients performed to date. Our data support donor origin for early BKV infection in kidney transplant recipients, and suggest that a specific HLA C locus may be associated with failure to control BKV infection.