Background: The role of cytomegalovirus (CMV) in cancer development after transplantation remains uncertain. We aimed to determine the association between donor and recipient CMV serological status and the risk of cancer development after kidney transplantation. Methods: Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry, we assessed the association between CMV donor/recipient (D/R) serological status and the risk of solid organ cancers in primary adult deceased-donor kidney transplant patients between 1990 and 2012. Results: Of 8140 recipients, a total of 895 (11%) recipients developed incident cancers during a follow-up time of 51 555 person-years. Human leukocyte antigen (HLA) mismatches was an effect modifier between CMV serological status and cancer (P=.03 for interaction). In recipients who have received 0-2 HLA-ABDR mismatched kidneys, the adjusted hazard ratios for cancer incidence among those with CMV D−/R−, CMV D−/R+, and CMV D+/R− were 0.47 (95% confidence interval [CI]: 0.24-0.91), 1.42 (95% CI: 0.97-2.07), and 1.02 (95% CI: 0.67-1.57), respectively compared with the reference of CMV D+/R+. A similar association was not observed in those with >2 HLA-ABDR mismatches. Conclusion: CMV D−/R− status was associated with a reduced risk of cancer in kidney transplant recipients who have received well-matched renal allografts, suggesting a potential role of HLA matching in cancer development.