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Posttransplant non-Hodgkin lymphoma is a rare complication but associated with high mortality. The extent to which human leukocyte antigen (HLA) mismatching influences the rate of posttransplant lymphoma has not been clarified.Data on lymphomas occurring in the first 3 years posttransplant were analyzed among first kidney transplants from deceased donors performed between 1985 and 2007 and reported to the Collaborative Transplant Study.Of 152,728 patients included, 593 non-Hodgkin lymphomas were diagnosed. Cox multivariate regression analysis showed that HLA-A mismatches had no influence on the rate of lymphoma. One and two HLA-DR mismatches were associated with a hazard ratio (HR) of 1.21 (95% confidence interval 1.00–1.45, P=0.047) and 1.56 (95% confidence interval 1.21–1.99, P<0.001), respectively. For lymphoma of the kidney and central nervous system, HRs for two HLA-DR mismatches were 2.29 (P=0.007) and 2.17 (P=0.029), respectively. Two HLA-B mismatches were also significantly associated with lymphoma in the kidney (HR 2.82, P=0.009).Mismatches at the HLA-DR locus are a significant risk factor for posttransplant non-Hodgkin lymphoma, particularly in the kidney and central nervous system, whereas two HLA-B mismatches increase the risk for the development of lymphoma of the kidney.