BK polyomavirus (BKV) causes nephropathy in kidney transplant recipients (KTRs). The virus has also been implicated as a possible cause of bladder and kidney cancers. Two KTRs who developed BKV nephropathy followed by renal carcinoma both showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major coat protein. The appearance and disappearance of these mutations over time suggests intra-patient evolution of the virus. Some of the observed mutations conferred resistance to antibody-mediated neutralization. The mutations also modified the spectrum of receptor glycans the virus engages during the infectious entry process. Nearly all observed mutations are consistent with DNA damage caused by APOBEC3B, an antiviral cytosine deaminase. This is intriguing in light of a recent report showing that BKV induces APOBEC3B expression. The results indicate that polyomaviruses can employ APOBEC3B to acquire beneficial site-specific mutations, conceivably with carcinogenic consequences for the host.