The virtual crossmatch (virtual‐XM) has been proposed for accurate identification of donor‐specific HLA‐antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual‐XM. In patients with a negative virtual‐XM (n = 190, 82%), prospective cytotoxicity crossmatches (CDC‐XM) were omitted, and they received standard immunosuppression. Virtual‐XM positive patients were only transplanted if CDC‐XM were negative. They received additional induction with anti‐T‐lymphocyte‐globulin and intravenous immunoglobulins (n = 43, 18%). The cumulative incidence of clinical/subclinical antibody‐mediated rejection (AMR) at 1 year was lower in the negative virtual‐XM than in the positive virtual‐XM group [15/190 (8%) vs. 18/43 (42%); P < 0.0001]. After a median follow‐up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual‐XM group (1% vs. 7%; P = 0.04) and death‐censored allograft survival at 2 years was higher (98% vs. 91%; P = 0.02). Serum creatinine was not different at the last follow‐up (129 μm vs. 130 μm; P = 0.58). We conclude that a negative virtual‐XM defines patients at low risk for AMR and early allograft loss, while a positive virtual‐XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual‐XM for risk stratification and treatment allocation.